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The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone
Accepted Manuscript The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone Lucia De Gregorio, MD, Carrie C. Lubitz, MD, MPH, FACS, Richard A. Hodin, MD, FACS, Randall D. Gaz, MD, FACS, Sareh Parangi, MD, FACS, Roy Phitayakorn, MD, FACS, Antonia E. Stephen, MD, FACS PII:
S1072-7515(16)00032-6
DOI:
10.1016/j.jamcollsurg.2015.12.048
Reference:
ACS 8162
To appear in:
Journal of the American College of Surgeons
Received Date: 22 October 2015 Revised Date:
2 December 2015
Accepted Date: 15 December 2015
Please cite this article as: De Gregorio L, Lubitz CC, Hodin RA, Gaz RD, Parangi S, Phitayakorn R, Stephen AE, The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone, Journal of the American College of Surgeons (2016), doi: 10.1016/j.jamcollsurg.2015.12.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone
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Lucia De Gregorio, MD, Carrie C Lubitz, MD, MPH, FACS, Richard A Hodin, MD, FACS, Randall D Gaz, MD, FACS, Sareh Parangi, MD, FACS, Roy Phitayakorn, MD, FACS, Antonia
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E Stephen, MD, FACS
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Department of Surgery, Massachusetts General Hospital, Boston, MA
Disclosure Information: Nothing to disclose.
Acknowledgments: This study was supported by the Alfonso Martin Escudero Foundation Research Grant, Madrid, Spain.
September 2015.
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Presented at the 96th Annual Meeting of the New England Surgical Society, Newport, RI,
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Correspondence address: Antonia E. Stephen, MD Division of Surgical Oncology 55 Fruit Street Yawkey 7B Boston, MA 02114 617-726-0531 [email protected]
Running head: The Truth about Double Adenomas
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ABSTRACT Background Double adenoma is reported in 3-12% of patients with primary hyperparathyroidism. The aim
localization studies and IOPTH assay in these cases. Study Design
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of this study is to determine the true incidence of double adenoma and analyze the utility of
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Retrospective review of a series of consecutive parathyroid surgical operations, from 2010 to 2013. According to the surgical findings, the series was divided into single gland disease (SGD),
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double gland disease (DGD) and multi-gland disease (MGD, more than two glands). The sensitivity of ultrasound (US), 99mTechnethium-sestamibi (MIBI) and 4-dimensional computerized tomography (4DCT) to correctly lateralize each gland in the DGD group was calculated. The results of the IOPTH assay, and how this impacted the extent of surgery, were
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analyzed. Results
347 patients had SGD (69%), 68 patients had DGD (13.5%) and 86 had MGD (17%). In the
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DGD group, sensitivity of US, MIBI and 4DCT to lateralize each adenoma was 42%, 34.5% and 64%, respectively. Initially, 27 patients (40%) with DGD had been planned for a focal
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exploration. The conversion to bilateral neck exploration was due to the IOPTH assay in 18 cases (two thirds of the initially planned focal explorations). At six month follow up, all DGD patients were normocalcemic. Conclusions
Localization studies in DGD can be misleading by reporting SGD. 4DCT seems to have the highest sensitivity. In focal explorations, the excision of all hyperfunctioning parathyroid tissue
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should be verified by IOPTH measurement.
- HPT: Hyperparathyroidism - pHPT: Primary Hyperparathyroidism - PTH: Parathyroid hormone
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- SGD: Single gland disease
- BNE: Bilateral neck exploration - US: Ultrasound
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- DGD: Double gland disease - MGD: Multi-gland disease
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ABREVIATIONS:
- MIBI: 99mTechnethium-sestamibi Single Photon Emission Computerized
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Tomography
- 4DCT: Four dimensional Computerized Tomography
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- IOPTH: Intraoperative Parathyroid Hormone assay
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INTRODUCTION The incidence of primary hyperparathyroidism (pHPT) is approximately 100,000 new cases per year. 1 Surgery is the only curative treatment for pHPT. 2 The reported incidence of multi-
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gland disease varies widely in the literature 3-7 and the existence of double adenomas has been questioned. 8,9 However, there is substantial published evidence that some patients with primary
do not experience persistent or recurrent disease. 3,4,6,10-16
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hyperparathyroidism have two abnormal glands removed at surgery and on long term follow up
Multi-gland disease and double adenoma represent a challenge in the management of pHPT,
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from the interpretation of the preoperative localization studies to deciding the extent of exploration and excision. At the present time, there is no clinical or biochemical feature that can consistently predict the existence of multi-gland disease in patients with sporadic pHPT. Preoperative localization studies are notoriously unreliable at accurately predicting multi-gland
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parathyroid enlargement, leaving surgeons to rely on intra-operative findings and clinical judgment in treating patients with pHPT and more than one abnormal gland. In this study, we aimed to (1) analyze the incidence and outcomes of patients with two
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abnormal glands resected during surgery at our institution, as well as to (2a) evaluate the performance of preoperative imaging studies and (2b) the intra-operative parathyroid hormone
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assay in this setting.
MATERIALS AND METHODS Patient selection
We utilized a prospectively maintained endocrine surgical database and reviewed 1076 consecutive parathyroid surgical cases, corresponding to 1064 patients, from January 2010 through December 2013. All data were obtained with institutional Internal Review Board
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approval at the Massachusetts General Hospital. Patients included in the study had a pre-operative diagnosis of pHPT undergoing a first-time operation with a postoperative follow up of at least six months. Patients known to have MEN
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syndrome were excluded. Patients who had a first-degree family member with HPT not related to MEN syndrome were not excluded from our study. Demographic data, Body Mass Index (BMI), preoperative and postoperative levels of serum calcium, ionized calcium, intact PTH (PTH),
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phosphorus, 25-hydroxy vitamin D3, creatinine; as well as preoperative 24 hour urinary calcium, were registered.
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504 cases that met the inclusion criteria were reviewed. Patients were classified into three groups: patients who had only one pathologic gland excised (single gland disease group), patients that had two enlarged glands excised (double gland disease group), and patients that had three or more abnormal glands excised (multi-gland disease group). Patients with an adenoma
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and a normal-appearing gland removed or biopsied were considered part of the single gland disease (SGD) group. Demographic and preoperative biochemical parameters from the double
groups. Imaging
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gland disease (DGD) group were compared to those in the SGD and multi-gland disease (MGD)
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The remaining information focuses on the DGD group. Patients were preoperatively studied by ultrasound (US), 99mTechnethium sestamibi SPECT (MIBI) and/or four dimensional computerized tomography (4DCT). The pre-operative imaging reports were classified as “positive”, when at least one abnormal gland was detected or “negative” when no abnormal gland was identified. When the localization study was positive, it could be indicative of SGD or DGD. In cases in which the imaging reported DGD, it could indicate unilateral or bilateral
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parathyroid enlargement. These results were compared with the operative findings, and the sensitivity of the tests was calculated. An abnormal gland intra-operatively that was correctly lateralized by the imaging study was considered a true positive. An abnormal gland intra-
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operatively identified but not detected by the localization study was considered a false negative. When an imaging study identified a gland as abnormal but the gland was found to be normal intra-operatively, it was considered a false positive. Since not all patients had a bilateral neck
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exploration with four gland assessment, true negative glands on imaging studies could not be
lateralizing the same abnormal glands. Operative and pathology reports
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calculated. Whenever two tests were positive, we assessed if the studies’ findings agreed in
From the operative reports, we recorded the preoperative intended approach, which was reported in the first paragraph of each operative note. When two imaging studies were positive
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and concordant for SGD, a focal surgical approach was attempted unless the patient had a thyroid condition that obliged a bilateral neck exploration. If the IOPTH levels did not drop appropriately after a focal exploration, the exploration was extended. On the other hand, patients
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with inconclusive imaging results or imaging that was suspicious for multi-gland disease were planned for a bilateral exploration.
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The protocol for IOPTH monitoring consisted of a baseline determination of serum PTH before the induction of anesthesia. PTH was again measured 10-15 minutes post-excision of the suspicious parathyroid gland or glands. The determination of intraoperative intact PTH was done by immunoassay analyzer Roche Cobas e601. An exploration was considered successful if the PTH dropped by 50% or more and into the normal reference range after the excision of the abnormal gland or glands.
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In all DGD patients, the weight (mg) and greatest diameter (mm) measured by the pathologist were recorded. The largest by weight of the two glands was labeled as “adenoma 1” and the smallest but still enlarged gland as “adenoma 2”. The macroscopic appearance of the glands
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during the surgical exploration, as subjectively assessed by the surgeon, split DGD patients into two categories: “symmetric” or “asymmetric” enlargement. The glandular weight and maximum diameter of these subgroups were compared.
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Clinical outcomes
Our definition of cure was normocalcemia maintained over all laboratory check-ups after
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surgery, with a minimum requirement of six months. Hypocalcemia was defined as serum calcium levels under the normal reference values, whether the patient was symptomatic or not. Postoperative hypocalcemia was considered permanent if it persisted after six months of follow up.
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Analysis
Normal ranges of biochemical parameters were 8.5–10.5 mg/dL for serum calcium, 1.14 1.30 nmol/L for serum ionized calcium, 10–60 pg/mL for serum PTH, 2.6–4.5 mg/dL for serum
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phosphorus, 33–100 ng/mL for serum 25-hydroxy vitamin D3 and 0.6–1.5 mg/dL for serum creatinine. The reference range for a normal 24 hour urinary excretion of calcium was up to 300
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mg/24h. Statistical analysis was performed using JMP® Pro version 11.0.0 (Copyright © 2013 SAS Institute Inc.). Age, BMI, biochemical parameters, and parathyroid gland weight and diameter, were treated as continuous variables. All other variables were considered categorical. Mean and standard deviation were calculated for age and BMI and median and interquartile range were used for the non-parametric variables. Categorical variables were compared using Chi-square test and Fisher’s exact test. Continuous variables were compared using Student’s
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ttest, ANOVA and Wilcoxon’s rank sum test. P value of less than 0.05 was considered statistically significant. RESULTS.
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Between January 2010 and December 2013, 504 patients operated on for pHPT met the
inclusion criteria described previously: first-time operation for primary HPT, follow up of at least six months, and no MEN syndrome. The majority of excluded patients were done so for
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inadequate length of follow up. Patients were operated on by seven endocrine surgeons. At
surgical exploration, 347 patients were noted to have one abnormal gland (SGD group, 68.8%),
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68 patients had two abnormal glands (DGD group, 13.5%) and 86 had three or more glands enlarged (MGD group, 17.1%). In 3 patients (0.6%), no abnormal parathyroid gland was found and the procedure was terminated without finding the culprit gland. The single gland disease (SGD) group included one case of parathyroid carcinoma (0.4%) and seven cases of atypical
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adenoma (1.4%). In the DGD group, 44 patients (64.7%) had the two adenomas on two different sides and the other 24 patients had adenomas on the same side. The mean age of the patients in this series was 60.6 ± 12.3 years. There were 397 females
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(79.2%) and 104 males (20.8%). The female:male ratio was 3.8:1. We found a significant difference between the mean age of the three groups, with a greater mean age in the multi-gland
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disease (MGD) group compared to SGD and DGD groups (p=0.023). There was no difference in age between SGD and DGD groups (p=0.68). We did not find any differences in gender distribution or BMI between the three groups (see Table 1). A comparison between the preoperative biochemical parameters among the three groups is shown on Table 2. Localization studies for double gland disease Localization studies for DGD group (68 patients) included 67 US, 55 MIBI and 14 4DCT. 41
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patients (60.3%) had an US and a MIBI, while 13 patients (19.1%) had US, MIBI and 4DCT. Twelve patients (17.6%) were studied by means of US alone, one patient had only a MIBI (1.5%) and another patient had US and 4DCT (1.5%).
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US correctly lateralized (true positives) 56 glands out of the 134 glands that could have been identified by this technique, failed to identify 75 glands and wrongly localized three glands that
abnormal gland in patients with DGD was 41.8%.
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were found to be normal on surgical exploration. US sensitivity to individually detect an
Fifty five patients had a MIBI. There were 38 true positive glands, 69 false negatives, and
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three falsely identified as abnormal glands. Sensitivity of MIBI to lateralize each individual gland in this group of DGD patients was 34.5%.
4DCT was done in 14 patients. In summary, 4DCT had 18 true positives glands, nine false negatives and one false positive. 4DCT’s sensitivity for each individual gland was 64.3%. On
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Table 3 a summary of imaging outcomes is shown.
Regarding the concordance of paired studies, 54 patients had US and MIBI. From those 54 cases, 27 had two positive results (50%), of which 15 of them agreed on the same side. These 15
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cases reported SGD and were accurate for the gland they described, but missed the second gland. The combination of US plus 4DCT was performed in 14 cases. In seven cases, both US and
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4DCT were positive. However, only one of these agreed on the same location, which was again reported as SGD, correctly lateralizing that parathyroid but missing the second pathologic gland. Thirteen patients had a MIBI and a 4DCT. Both reports were positive in seven cases, of which five agreed in the same side: four reported SGD but one suggested bilateral DGD. They both correctly lateralized six glands and missed four. The percentages of concordance of paired imaging exams were 27.8% for US-MIBI, 7.1% for US-4DCT and 38.5% for MIBI-4DCT. From
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the 68 patients with DGD, 20 had two studies concordant for SGD and only one patient had a correct preoperative diagnosis of DGD by the combination of MIBI and 4DCT. Surgical explorations and IOPTH assay
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From the 504 patients included in the review, 64.3% of the cases (324) consisted of a bilateral neck exploration (BNE), 104 patients (20.6%) underwent a unilateral exploration and 76 (15.1%) a focal exploration. There was a significant difference between the BNE rate in the three groups,
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which was 49.6% for SGD group, 92.6% for DGD group and 100% for MGD group (p<0.001). An IOPTH assay was performed in 94.4% of the cases (93.4% of SGD, 100% of DGD and
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95.3% of MGD; p=0.052). At least one parathyroid tissue sample was sent for intraoperative frozen section in 82.7% of the patients (81.3% of SGD group, 83.8% of DGD and 87.2% of MGD; p=0.44). Parathyroid glands judged as normal by the operating surgeon were not routinely biopsied.
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In the DGD group (n=68), 41 cases (60.3%) had a BNE as initial surgical plan. Seven of these patients (10.3%) had a total thyroidectomy performed at the same surgical procedure. Twenty seven patients (39.7%) had an initial surgical plan of focal exploration. Intraoperative
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measurements of PTH assay were performed in all 68 cases of DGD. In most cases it was performed after the surgical exploration was completed and both abnormal glands had been
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removed, as a confirmation that there was no remaining hyperfunctioning tissue. In 66 patients, the final PTH measurement at the end of the procedure fell greater than 50% from baseline values and into the normal reference range. There were two cases in which, after assessing all four glands and removing the two enlarged ones, PTH did not meet these criteria. In these two cases, the baseline PTH was 62 pg/ml and 77 pg/ml, respectively, and the final PTH fell down into the normal reference values but did not reach a decrease of greater than 50% from baseline
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(31 pg/ml and 52 pg/ml, respectively). Both patients were normocalcemic with normal PTH levels on six months post-operative follow up. There were 24 DGD cases (35.3%) in which the IOPTH assay was carried out after the
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removal of one abnormal gland, and in all of these cases PTH did not drop into the normal range, prompting an extension of the surgical exploration until a second abnormal gland was found. After the removal of the second gland, the PTH did drop appropriately in all 24 cases. Sixty three
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patients (92.6%) in the DGD group ultimately had a BNE. From the 27 planned focal
explorations, 22 were extended to a BNE. In four cases, this change of strategy was due to the
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operative findings, notably the appearance of the initially explored gland(s), leading the surgeon to suspect multi-gland disease. The IOPTH assay results determined the change in surgical approach in the other 18 cases. Therefore, from the 27 cases in which the surgical strategy had to be modified, IOPTH was the driver of an extended exploration in two thirds of these. There were
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only five cases whose surgical procedure was limited to a unilateral exploration. In these, IOPTH assay was performed after finding and removing two abnormal glands and PTH dropped appropriately. Therefore, their exploration was not extended. Figure 1 describes the change of
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surgical strategy that occurred in the various cases. Surgeons’ assessment and surgical pathology
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The median maximum gland diameter and interquartile range of the whole series was 14 mm [10 – 17] and the median gland weight was 383 mg, IQR [200 – 700]. There were significant differences among the three groups in regards to gland size, where SGD group had the largest and heaviest glands and MGD had the smallest and lightest glands (SGD median length of glands: 15 mm, IQR: [12 – 20] vs. DGD median length of glands: 12 mm, IQR: [9 – 15] vs. MGD median length of glands: 10 mm, IQR: [8 – 13]; p<0.001. SGD median weight of glands:
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500 mg, IQR: [269 – 880] vs. DGD median weight of glands: 250 mg, IQR [165 – 507] vs. MGD median weight of glands: 170 mg, IQR: [88 -310], p<0.001). In half of the DGD cases (34 patients) the surgeon stated an asymmetric enlargement of the
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abnormal glands, identifying one gland as the “dominant” adenoma. In the remaining cases, the surgeon did not report a major difference in the sizes of the two excised glands. The DGD cases were divided into 2 categories: symmetric and asymmetric. The pathologic data confirmed the
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surgeons’ observations: the “asymmetric adenoma 1” were significantly heavier and larger than the “asymmetric adenoma 2” (p=0.014) and no differences were found between “symmetric
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adenoma 1” compared to “symmetric adenoma 2” (p=0.151, results not shown in table). When comparing the weights and sizes of the symmetric versus the asymmetric enlarged glands, we found a significant difference (p=0.025) in the length of “adenoma 1” in the asymmetric group but not on the glandular weight (p=0.113) compared to “adenoma 1” in the symmetric group.
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There was also no statistical significant difference among the adenoma 2 in the symmetric and asymmetric groups (see Table 4). The presence of a “dominant” gland assessed by the surgeons in the asymmetric group matched what the pathologist measured. Nonetheless, the smallest gland
Surgical outcomes
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in the asymmetric group was not different from any of the glands in the symmetric group.
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The median follow up of the complete series was 26.1 months (IQR [13.7 – 38]). The latest postoperative biochemical values revealed a median serum calcium of 9.5 mg/dL, IQR: [9.2 – 9.8]; median serum ionized calcium: 1.23 mmol/dL, IQR: [1.18 – 1.27]; median serum PTH: 45 pg/mL, IQR: [34 – 58.2]; median serum phosphorus: 3.1 mg/dL, IQR: [2.7 – 3.5]; median serum 25-hydroxy vitamin D3: 36 ng/mL, IQR: [29 – 45]; and median serum creatinine: 0.85 mg/dL, IQR: [0.71 – 1.02]. There were no differences between the postoperative biochemical values
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among the three groups, except for the serum creatinine, which was slightly higher in the MGD group compared to the SGD group (SGD: 0.83 mg/dl, IQR: [0.7 – 1] vs. MGD: 0.88 mg/dL, IQR: [0.76 – 1.18]; p=0.02).
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The cure rate after surgery was 95%. The MGD group had a significantly lower cure rate compared to the other two groups (SGD: 96.8% vs. DGD group: 100% vs. MGD: 83.7%;
p<0.001). The difference in cure rate between SGD and DGD was not statistically significant
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(p=0.22). One hundred one patients (20.2%) had a persistently elevated serum PTH with normal serum calcium postoperatively. The percentages of postoperative normocalcemic HPT did not
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differ significantly among the three groups (SGD: 18.7% vs. DGD: 22.1% vs. MGD: 24.4%; p=0.434). Two of these patients (both SGD) were found to have a recurrence of disease after an apparently curative BNE with one gland removed.
After at least six months of follow up, all DGD patients remained eucalcemic with a median
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serum calcium of 9.6 mg/dl (IQR [9.2 – 9.9]) and median serum PTH of 44 pg/mL (IQR [33 – 58]). There were 15 DGD patients with elevated postoperative PTH levels and calcium levels well within the normal range. For these 15 patients, the median PTH was 70 pg/mL (IQR [51 –
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85]) and median postoperative calcium was 9.6 mg/dL (IQR [9.4 -9.8]). Three of these patients had mild chronic kidney disease.
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In the whole series, 35 patients (6.9%) presented with postoperative hypocalcemia. There were no differences in the hypocalcemia rates between the surgical approaches (BNE, unilateral neck exploration). Of these 35 patients, four of them were still dependant on oral calcium supplements six months after surgery (permanent hypocalcemia of 0.8%). However, the MGD group had the highest percentage of postoperative hypocalcemia (SGD: 5.8% vs. DGD: 2.9% vs. MGD: 15.1%; p=0.007). There was one case (0.2%) of neck hematoma that required emergent
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re-operation for evacuation. This patient had SGD but a concurrent total thyroidectomy. Another case (0.2%) was complicated by a transient unilateral vocal cord paralysis that fully recovered three months post-operatively.
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DISCUSSION
In our opinion, “double adenoma” is a real clinical entity that can result in difficult operative situations and failed explorations. Although relatively uncommon compared to single gland
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disease, it should be considered in patients undergoing surgery for primary hyperparathyroidism. This is evidenced in our series of patients with two removed glands and surgical cure with a
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considerable length of post-operative follow up (median of 26 months), during which time we are able to say that so far the 68 patients with DGD in our series have not presented with recurrence or persistence of disease. As Milas and colleagues 4 described in their study, during the past decades there has been an increase in the reported incidence of double adenoma, which
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is likely attributable to the greater awareness of this entity by surgeons and the widespread use of IOPTH during cervical explorations. In our series we found a higher incidence of double adenoma than most authors (13.5%), 3,6,8,10,12,14,17,18 but similar to that reported in more recent
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studies. 4,7,15
Most groups have found that a bilateral distribution of the two adenomas is more common
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than unilateral. 3,4,6,12,15-17 In our case, we found that almost 65% of the cases followed this pattern. We did not find any differences in regard to gender distribution. Kandil 6 found that double adenoma was proportionally more common in men, while Szabo 15 observed a greater proportion of female patients in their SGD group compared to the percentage of females with double or multi-gland disease. Regarding age, we found that patients with a final diagnosis of MGD were older than patients with SGD and DGD. In contrast, another study found that DGD
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was associated with older age. 16 In a different publication by the same group, an association was found between older age and recurrence or persistence of HPT due to DGD, compared to recurrence or persistence due to MGD. 19
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Many studies have documented that localization studies are generally inaccurate in cases of multi-gland disease. 4,12,16,20 Haciyanli 3 published the most optimistic study regarding the
combined results of US, MIBI and IOPTH in patients with double adenoma. They found that
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80% of the cases had a diagnosis of double adenoma by at least one of the tests, US or MIBI or IOPTH. We observed that it was uncommon for any imaging modality to simultaneously and
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accurately lateralize both abnormal glands. There was only one case where MIBI and 4DCT were concordant for the same two glands. However, the high rates of negative, inconclusive or discordant tests resulted in a positive outcome for patients with DGD, since these poorly defined pre-operative imaging reports drove the decision towards a BNE. The real challenge came for
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those DGD patients who had conclusive and even concordant studies indicating SGD. It was in these patients where IOPTH played a crucial role guiding the surgeons until they had resected all hyperfunctioning glands. In our series, approximately 40% of the DGD patients fell into this
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risky group and IOPTH “saved” them from an unsuccessful parathyroidectomy. Our experience with the use of IOPTH was excellent and better than what other authors have reported, 3,4,6,7,14,20
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as in no case did it drop until both adenomas had been removed. Similarly to what Milas and colleagues did in their study, 4 we divided our DGD patients depending on the symmetry of the two enlarged glands. The asymmetry between the two glands assessed by the surgeons was supported by the differences in weight and maximum diameter measured by the pathologists. In general terms, we could say that half of the patients had two similarly enlarged glands and the other half had a larger gland accompanied by a smaller but still
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abnormal gland. Although we did not look specifically at which of the glands was removed first (largest or smallest), in no case, independent of which subgroup the patient belonged to, did the IOPTH fall until both abnormal glands had been removed. In Milas’ study, the authors observed
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a greater percentage of false positive IOPTH drop in cases of asymmetric enlargement where the largest gland had been removed first, not predicting the presence of a second enlarged gland. 4 In our series, only 35% of DGD cases had an IOPTH assay after one first gland had been removed.
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It is possible that we would have found more false positive results in the IOPTH assay if we had performed the test before the resection of the second abnormal gland more often.
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There are some limitations to our study. First we must acknowledge its retrospective nature, as well as the variation in surgical practices and operative report dictation among the seven surgeons who contributed in this series. Fortunately, the majority of the operative reports were formatted in a standardized fashion. A summary of the patients’ history and the initial surgical
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plan was clearly reflected in the opening paragraph. With regards to the surgeons’ approach to normal-appearing glands, most were inspected and determined to be normal based on the size, color, and texture of the gland. Only in rare circumstances were normal glands biopsied. There
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were 14 cases of SGD were a second gland was entirely removed, based on the initial assessment of the glands’ appearance, but after removal the surgeon clearly stated in the operative report that
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the gland appeared normal and this was corroborated by the intraoperative frozen section. Most surgeons described each explored gland in the operative report and explained how their decisions were or were not influenced by the IOPTH assay or the results of the intraoperative frozen section. In addition to this, not all DGD had a BNE. Five patients had a unilateral exploration followed by an IOPTH drop after the removal of two enlarged glands. In these cases the surgeon decided not to extend the exploration. These patients remain eucalcemic. Nevertheless, we
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acknowledge that a BNE in the setting of two unilateral enlarged glands would have been the ideal course of action to ensure that the contralateral glands were normal. Another limitation of our study is that we restricted our analyzed patient population only to
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those with well-documented six months follow up laboratory values. This excluded almost half of the patients who underwent parathyroidectomy during the study time period. However, given the importance of the documentation of biochemical cure, we thought this was most appropriate.
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An additional issue that merits comment is that there were 101 patients (20.2%) with persistent post-operative elevation of serum PTH. Two of these patients have a documented recurrence,
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both of which had a single gland removed at the initial operation. Patients with an elevated PTH and normocalcemia after parathyroid surgery could have vitamin D deficiency, persistent pHPT with normocalcemia, or relative post-operative hypocalcemia with a need for additional calcium supplementation. More rigorous follow up of these patients would clearly be of benefit to better
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define the cause of the elevated PTH and treat accordingly.
The debate about the definition of parathyroid adenoma, hyperplasia and the existence of multiple adenomas has been ongoing for decades. 8,9,21,22 There is still no consensus about the
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pathological differentiating characteristics between adenomatous or hyperplasic parathyroid glands. 9,11,23 Despite the various techniques used by pathologists to try to determine the nature
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of a pathologic parathyroid gland, this distinction is difficult to define. 13,23-25 Adenomas are believed to be a monoclonal proliferation while hyperplasia is considered a polyclonal overgrowth of parathyroid tissue. However, monoclonality has been also observed in hyperplastic glands. 26,27 Cetani and colleagues 28 studied seven families with isolated familial HPT (with no other MEN associated conditions) and found MEN1 mutations in three of them and all of these were found to have MGD. Dwight 29 focused her analysis on five patients with
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double adenoma and observed different genetic changes in the two tumors of each patient, suggesting independent somatic mutations were the cause of multiple parathyroid tumors. 30% of these tumors had MEN1 loss of heterozigosity but these mutations were not present in all
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tumors within the same patient. As plausible explanations for these findings, the authors suggested the occurrence of different primary genetic events or the possibility that other
unknown factors could prompt several tumorigenic events in the same individual. 29 All these
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discoveries are promising and may help clarify the underlying pathogenesis of parathyroid
tumors. While this histological issue remains unsolved, it may be time to consider a change in
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nomenclature. As other authors have suggested, 15 we preferred to use the terms single, double or multi-gland disease in our analysis, independently of how the pathologist had described the specimens.
In summary, surgeons must be aware that up to a third of their patients could have two or
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more abnormal glands, even with preoperative imaging indicating SGD. In our experience, there is a considerable percentage of patients in which two abnormal glands are discovered during surgery and cure is achieved after resecting the enlarged glands. IOPTH has proven to be
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accurate in predicting postoperative normocalcemia. However, the experience of some groups with IOPTH in the presence of two or more enlarged glands raises the question of the
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significance of each gland in the hypersecretion of PTH. In treating and operating on patients with pHPT, surgeons must assemble the relevant pre-operative clinical information, localization studies, intra-operative findings and IOPTH results, in ultimately deciding the extent of operation and the removal of individual parathyroid glands. Until the insights of parathyroid enlargement and overproduction are better understood, surgeons must use their experience, judgment and skills in determining the best course of action in each individual patient.
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REFERENCES 1. Consensus development conference statement. J Bone Miner Res 1991;6:S9-13. 2. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic
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primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab 2014;99:3561-3569.
3. Haciyanli M, Lal G, Morita E, et al. Accuracy of preoperative localization studies and
double adenoma. J Am Coll Surg 2003;197:739-746.
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intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and
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4. Milas M, Wagner K, Easley KA, et al. Double adenomas revisited: Nonuniform distribution favors enlarged superior parathyroids (fourth pouch disease). Surgery 2003;134:995-1003; discussion 1003-1004.
5. Molinari AS, Irvin GL 3rd, Deriso GT, Bott L. Incidence of multiglandular disease in primary
discussion 936-937.
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hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996;120:934-936;
6. Kandil E, Alabbas HH, Bansal A, et al. Intraoperative parathyroid hormone assay in patients
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with primary hyperparathyroidism and double adenoma. Arch Otolaryngol Head Neck Surg 2009;135:1206-1208.
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7. Gordon LL, Snyder WH 3rd, Wians F Jr, et al. The validity of quick intraoperative parathyroid hormone assay: An evaluation in seventy-two patients based on gross morphologic criteria. Surgery 1999;126:1030-1035. 8. Wang CA, Rieder SV. A density test for the intraoperative differentiation of parathyroid hyperplasia from neoplasia. Ann Surg 1978;187:63-67.
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9. Ghandur-Mnaymneh L, Kimura N. The parathyroid adenoma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J Pathol 1984;115:70-83. 10. Attie JN, Bock G, Auguste LJ. Multiple parathyroid adenomas: Report of thirty-three cases.
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Surgery 1990;108:1014-1019; discussion 1019-1020.
11. Baloch ZW, LiVolsi VA. Double adenoma of the parathyroid gland: Does the entity exist? Arch Pathol Lab Med 2001;125:178-179.
double adenomas. J Am Coll Surg 2004;198:185-189.
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12. Bergson EJ, Heller KS. The clinical significance and anatomic distribution of parathyroid
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13. Bonjer HJ, Bruining HA, Birkenhager JC, et al. Single and multigland disease in primary hyperparathyroidism: Clinical follow-up, histopathology, and flow cytometric DNA analysis. World J Surg 1992;16:737-743; discussion 743-744.
14. Gauger PG, Agarwal G, England BG, et al. Intraoperative parathyroid hormone monitoring
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fails to detect double parathyroid adenomas: A 2-institution experience. Surgery 2001;130:10051010.
15. Szabo E, Lundgren E, Juhlin C, et al. Double parathyroid adenoma, a clinically nondistinct
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entity of primary hyperparathyroidism. World J Surg 1998;22:708-713. 16. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas. clinical and
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biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300-307discussion 307-309.
17. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995;82:926-929. 18. van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: An institutional perspective. World J Surg 1991;15:688-692.
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19. Tezelman S, Shen W, Siperstein AE, et al. Persistent or recurrent hyperparathyroidism in patients with double adenomas. Surgery 1995;118:1115-1122. 20. Genc H, Morita E, Perrier ND, et al. Differing histologic findings after bilateral and focused
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parathyroidectomy. J Am Coll Surg 2003;196:535-540.
21. Harness JK, Ramsburg SR, Nishiyama RH, Thompson NW. Multiple adenomas of the parathyroids: Do they exist? Arch Surg 1979;114:468-474.
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22. Cope O. Endocrine surgery. Surg Clin North Am 1978;58:957-966.
23. Grimelius L, Akerstrom G, Bondeson L, et al. The role of the pathologist in diagnosis and
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surgical decision making in hyperparathyroidism. World J Surg 1991;15:698-705. 24. Roth SI, Gallagher MJ. The rapid identification of "normal" parathyroid glands by the presence of intracellular fat. Am J Pathol 1976;84:521-528.
25. Yao K, Singer FR, Roth SI, et al. Weight of normal parathyroid glands in patients with
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parathyroid adenomas. J Clin Endocrinol Metab 2004;89:3208-3213. 26. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658-662.
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27. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995;95:2047-2053.
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28. Cetani F, Pardi E, Ambrogini E, et al. Genetic analyses in familial isolated hyperparathyroidism: Implication for clinical assessment and surgical management. Clin Endocrinol (Oxf) 2006;64:146-152. 29. Dwight T, Nelson AE, Theodosopoulos G, et al. Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism. Am J Pathol 2002;161:1299-1306.
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Table 1. General Description of the Series and Comparison Between Single Gland, Double Gland, and Multi-Gland Disease Groups SGD 347 68.9% 59.9 ± 12.6 268 77.2% 28.8 ± 6.5 14 4.0%
DGD 68 13.5% 60.6 ± 12.2 56 82.4% 28.5 ± 6.1 3 4.4%
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DGD, double gland; HPT, hyperparathyroidism; MGD, multi-gland; SGD, single gland.
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MGD 86 17.1% 63.9 ± 9.9 73 84.9% 27.8 ± 5.5 8 9.3%
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Total 504 60.6 ± 12.3 397 79.2% 28.6 ± 6.3 25 5%
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n, % Age, y, mean ± SD Female, n, % BMI, kg/m2, mean ± SD Familial history of HPT, n, % *Statistical significance.
p Value 0.023* 0.248 0.446 0.144
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Table 2. Three Group Comparison of Preoperative Biochemical Values SGD
DGD
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Total
MGD
p Value
IQR
Median
IQR
Median
IQR
Median
IQR
Serum calcium, mg/dL
10.9
[10.6 - 11.4]
11
[10.6 - 11.5]
10.9
[10.6 - 11.4]
10.7
[10.4 - 11.1]
<0.001*
Serum ionized calcium, nmol/dL
1.4
[1.35 - 1.46]
1.4
[1.35 - 1.47]
1.4
[1.35 - 1.49]
1.36
[1.32 - 1.44]
0.007*
Serum parathyroidism, pg/mL
101
[76.25 - 131]
104
[78 - 135.5]
97.5
[73.2 - 124.2]
93
[72.5 - 124.5]
0.080
Serum phosphorus, mg/dL
2.6
[2.2 - 3]
2.6
Serum vitamin D, ng/mL
35
[27 - 42]
34
Serum creatinine, mg/dL
0.84
[0.73 - 1]
0.82
24-h Urine calcium, mg
273.5
[162.2 - 369.7]
300
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2.7
[2.3 - 2.9]
2.8
[2.5 - 3.1]
<0.001*
[26 - 42]
33
[26 - 41]
39
[32 - 45.7]
0.004*
[0.71 - 0.94]
0.9
[0.76 - 1.02]
0.9
[0.76 - 1.15]
0.002*
[179.5 - 390]
228
[161 - 336]
171.5
[115.5 - 321.5]
0.001*
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*Statistical significance.
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Median
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DGD, double gland; IQR, interquartile range; MGD, multi-gland; SGD, single gland.
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Table 3. Results of Imaging Studies in Patients with Double-Gland Disease %
True positives
False negatives
False positives Sensitivity, %
US
67
98.5
56
75
3
41.8
MIBI
55
80.9
38
69
3
34.5
4DCT
14
20.6
18
9
1
64.3
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US, Ultrasound; MIBI, 99mTechnethium-Sestamibi SPECT; 4DCT, 4-dimension CT.
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n
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Table 4. Comparison between Symmetric and Asymmetric Enlarged Adenomas Resected from the Double Gland Disease Patients
Median
IQR
Asymmetric enlargement Median
Adenoma 1 254.5
[140 - 625]
370
[265 - 584]
0.113
Length, mm
11
[10 - 15]
15
[11.5 - 19]
0.025*
Weight, mg
194
[109 - 300]
110
[81.5 - 232]
0.134
Length, mm
11
[8 - 15]
[7.5 - 14]
0.345
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*Statistical significance.
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IQR, interquartile range.
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Weight, mg
Adenoma 2
25
IQR
p Value
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Symmetric enlargement
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Figure Legend Figure 1. Diagram showing the procedure flow of the double-gland disease patients. All 68 patients had 2 abnormal glands removed at surgical exploration. BNE, bilateral neck exploration; IoPTH,
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intraoperative parathyroid hormone assay; PTH, parathyroid hormone.
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Precis Retrospective review of a series of cases operated on for primary hyperparathyroidism and analysis of the incidence and outcomes of patients with two abnormal glands resected
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and the intra-operative parathyroid hormone assay in this setting.
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during surgery. Particular attention is dedicated to the role of preoperative imaging studies
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Figure 1.
S1072-7515(16)00032-6
DOI:
10.1016/j.jamcollsurg.2015.12.048
Reference:
ACS 8162
To appear in:
Journal of the American College of Surgeons
Received Date: 22 October 2015 Revised Date:
2 December 2015
Accepted Date: 15 December 2015
Please cite this article as: De Gregorio L, Lubitz CC, Hodin RA, Gaz RD, Parangi S, Phitayakorn R, Stephen AE, The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone, Journal of the American College of Surgeons (2016), doi: 10.1016/j.jamcollsurg.2015.12.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Truth about Double Adenomas: Incidence, Localization, and Intraoperative Parathyroid Hormone
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Lucia De Gregorio, MD, Carrie C Lubitz, MD, MPH, FACS, Richard A Hodin, MD, FACS, Randall D Gaz, MD, FACS, Sareh Parangi, MD, FACS, Roy Phitayakorn, MD, FACS, Antonia
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E Stephen, MD, FACS
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Department of Surgery, Massachusetts General Hospital, Boston, MA
Disclosure Information: Nothing to disclose.
Acknowledgments: This study was supported by the Alfonso Martin Escudero Foundation Research Grant, Madrid, Spain.
September 2015.
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Presented at the 96th Annual Meeting of the New England Surgical Society, Newport, RI,
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Correspondence address: Antonia E. Stephen, MD Division of Surgical Oncology 55 Fruit Street Yawkey 7B Boston, MA 02114 617-726-0531 [email protected]
Running head: The Truth about Double Adenomas
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ABSTRACT Background Double adenoma is reported in 3-12% of patients with primary hyperparathyroidism. The aim
localization studies and IOPTH assay in these cases. Study Design
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of this study is to determine the true incidence of double adenoma and analyze the utility of
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Retrospective review of a series of consecutive parathyroid surgical operations, from 2010 to 2013. According to the surgical findings, the series was divided into single gland disease (SGD),
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double gland disease (DGD) and multi-gland disease (MGD, more than two glands). The sensitivity of ultrasound (US), 99mTechnethium-sestamibi (MIBI) and 4-dimensional computerized tomography (4DCT) to correctly lateralize each gland in the DGD group was calculated. The results of the IOPTH assay, and how this impacted the extent of surgery, were
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analyzed. Results
347 patients had SGD (69%), 68 patients had DGD (13.5%) and 86 had MGD (17%). In the
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DGD group, sensitivity of US, MIBI and 4DCT to lateralize each adenoma was 42%, 34.5% and 64%, respectively. Initially, 27 patients (40%) with DGD had been planned for a focal
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exploration. The conversion to bilateral neck exploration was due to the IOPTH assay in 18 cases (two thirds of the initially planned focal explorations). At six month follow up, all DGD patients were normocalcemic. Conclusions
Localization studies in DGD can be misleading by reporting SGD. 4DCT seems to have the highest sensitivity. In focal explorations, the excision of all hyperfunctioning parathyroid tissue
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should be verified by IOPTH measurement.
- HPT: Hyperparathyroidism - pHPT: Primary Hyperparathyroidism - PTH: Parathyroid hormone
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- SGD: Single gland disease
- BNE: Bilateral neck exploration - US: Ultrasound
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- DGD: Double gland disease - MGD: Multi-gland disease
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ABREVIATIONS:
- MIBI: 99mTechnethium-sestamibi Single Photon Emission Computerized
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Tomography
- 4DCT: Four dimensional Computerized Tomography
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- IOPTH: Intraoperative Parathyroid Hormone assay
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INTRODUCTION The incidence of primary hyperparathyroidism (pHPT) is approximately 100,000 new cases per year. 1 Surgery is the only curative treatment for pHPT. 2 The reported incidence of multi-
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gland disease varies widely in the literature 3-7 and the existence of double adenomas has been questioned. 8,9 However, there is substantial published evidence that some patients with primary
do not experience persistent or recurrent disease. 3,4,6,10-16
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hyperparathyroidism have two abnormal glands removed at surgery and on long term follow up
Multi-gland disease and double adenoma represent a challenge in the management of pHPT,
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from the interpretation of the preoperative localization studies to deciding the extent of exploration and excision. At the present time, there is no clinical or biochemical feature that can consistently predict the existence of multi-gland disease in patients with sporadic pHPT. Preoperative localization studies are notoriously unreliable at accurately predicting multi-gland
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parathyroid enlargement, leaving surgeons to rely on intra-operative findings and clinical judgment in treating patients with pHPT and more than one abnormal gland. In this study, we aimed to (1) analyze the incidence and outcomes of patients with two
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abnormal glands resected during surgery at our institution, as well as to (2a) evaluate the performance of preoperative imaging studies and (2b) the intra-operative parathyroid hormone
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assay in this setting.
MATERIALS AND METHODS Patient selection
We utilized a prospectively maintained endocrine surgical database and reviewed 1076 consecutive parathyroid surgical cases, corresponding to 1064 patients, from January 2010 through December 2013. All data were obtained with institutional Internal Review Board
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approval at the Massachusetts General Hospital. Patients included in the study had a pre-operative diagnosis of pHPT undergoing a first-time operation with a postoperative follow up of at least six months. Patients known to have MEN
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syndrome were excluded. Patients who had a first-degree family member with HPT not related to MEN syndrome were not excluded from our study. Demographic data, Body Mass Index (BMI), preoperative and postoperative levels of serum calcium, ionized calcium, intact PTH (PTH),
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phosphorus, 25-hydroxy vitamin D3, creatinine; as well as preoperative 24 hour urinary calcium, were registered.
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504 cases that met the inclusion criteria were reviewed. Patients were classified into three groups: patients who had only one pathologic gland excised (single gland disease group), patients that had two enlarged glands excised (double gland disease group), and patients that had three or more abnormal glands excised (multi-gland disease group). Patients with an adenoma
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and a normal-appearing gland removed or biopsied were considered part of the single gland disease (SGD) group. Demographic and preoperative biochemical parameters from the double
groups. Imaging
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gland disease (DGD) group were compared to those in the SGD and multi-gland disease (MGD)
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The remaining information focuses on the DGD group. Patients were preoperatively studied by ultrasound (US), 99mTechnethium sestamibi SPECT (MIBI) and/or four dimensional computerized tomography (4DCT). The pre-operative imaging reports were classified as “positive”, when at least one abnormal gland was detected or “negative” when no abnormal gland was identified. When the localization study was positive, it could be indicative of SGD or DGD. In cases in which the imaging reported DGD, it could indicate unilateral or bilateral
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parathyroid enlargement. These results were compared with the operative findings, and the sensitivity of the tests was calculated. An abnormal gland intra-operatively that was correctly lateralized by the imaging study was considered a true positive. An abnormal gland intra-
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operatively identified but not detected by the localization study was considered a false negative. When an imaging study identified a gland as abnormal but the gland was found to be normal intra-operatively, it was considered a false positive. Since not all patients had a bilateral neck
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exploration with four gland assessment, true negative glands on imaging studies could not be
lateralizing the same abnormal glands. Operative and pathology reports
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calculated. Whenever two tests were positive, we assessed if the studies’ findings agreed in
From the operative reports, we recorded the preoperative intended approach, which was reported in the first paragraph of each operative note. When two imaging studies were positive
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and concordant for SGD, a focal surgical approach was attempted unless the patient had a thyroid condition that obliged a bilateral neck exploration. If the IOPTH levels did not drop appropriately after a focal exploration, the exploration was extended. On the other hand, patients
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with inconclusive imaging results or imaging that was suspicious for multi-gland disease were planned for a bilateral exploration.
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The protocol for IOPTH monitoring consisted of a baseline determination of serum PTH before the induction of anesthesia. PTH was again measured 10-15 minutes post-excision of the suspicious parathyroid gland or glands. The determination of intraoperative intact PTH was done by immunoassay analyzer Roche Cobas e601. An exploration was considered successful if the PTH dropped by 50% or more and into the normal reference range after the excision of the abnormal gland or glands.
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In all DGD patients, the weight (mg) and greatest diameter (mm) measured by the pathologist were recorded. The largest by weight of the two glands was labeled as “adenoma 1” and the smallest but still enlarged gland as “adenoma 2”. The macroscopic appearance of the glands
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during the surgical exploration, as subjectively assessed by the surgeon, split DGD patients into two categories: “symmetric” or “asymmetric” enlargement. The glandular weight and maximum diameter of these subgroups were compared.
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Clinical outcomes
Our definition of cure was normocalcemia maintained over all laboratory check-ups after
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surgery, with a minimum requirement of six months. Hypocalcemia was defined as serum calcium levels under the normal reference values, whether the patient was symptomatic or not. Postoperative hypocalcemia was considered permanent if it persisted after six months of follow up.
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Analysis
Normal ranges of biochemical parameters were 8.5–10.5 mg/dL for serum calcium, 1.14 1.30 nmol/L for serum ionized calcium, 10–60 pg/mL for serum PTH, 2.6–4.5 mg/dL for serum
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phosphorus, 33–100 ng/mL for serum 25-hydroxy vitamin D3 and 0.6–1.5 mg/dL for serum creatinine. The reference range for a normal 24 hour urinary excretion of calcium was up to 300
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mg/24h. Statistical analysis was performed using JMP® Pro version 11.0.0 (Copyright © 2013 SAS Institute Inc.). Age, BMI, biochemical parameters, and parathyroid gland weight and diameter, were treated as continuous variables. All other variables were considered categorical. Mean and standard deviation were calculated for age and BMI and median and interquartile range were used for the non-parametric variables. Categorical variables were compared using Chi-square test and Fisher’s exact test. Continuous variables were compared using Student’s
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ttest, ANOVA and Wilcoxon’s rank sum test. P value of less than 0.05 was considered statistically significant. RESULTS.
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Between January 2010 and December 2013, 504 patients operated on for pHPT met the
inclusion criteria described previously: first-time operation for primary HPT, follow up of at least six months, and no MEN syndrome. The majority of excluded patients were done so for
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inadequate length of follow up. Patients were operated on by seven endocrine surgeons. At
surgical exploration, 347 patients were noted to have one abnormal gland (SGD group, 68.8%),
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68 patients had two abnormal glands (DGD group, 13.5%) and 86 had three or more glands enlarged (MGD group, 17.1%). In 3 patients (0.6%), no abnormal parathyroid gland was found and the procedure was terminated without finding the culprit gland. The single gland disease (SGD) group included one case of parathyroid carcinoma (0.4%) and seven cases of atypical
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adenoma (1.4%). In the DGD group, 44 patients (64.7%) had the two adenomas on two different sides and the other 24 patients had adenomas on the same side. The mean age of the patients in this series was 60.6 ± 12.3 years. There were 397 females
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(79.2%) and 104 males (20.8%). The female:male ratio was 3.8:1. We found a significant difference between the mean age of the three groups, with a greater mean age in the multi-gland
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disease (MGD) group compared to SGD and DGD groups (p=0.023). There was no difference in age between SGD and DGD groups (p=0.68). We did not find any differences in gender distribution or BMI between the three groups (see Table 1). A comparison between the preoperative biochemical parameters among the three groups is shown on Table 2. Localization studies for double gland disease Localization studies for DGD group (68 patients) included 67 US, 55 MIBI and 14 4DCT. 41
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patients (60.3%) had an US and a MIBI, while 13 patients (19.1%) had US, MIBI and 4DCT. Twelve patients (17.6%) were studied by means of US alone, one patient had only a MIBI (1.5%) and another patient had US and 4DCT (1.5%).
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US correctly lateralized (true positives) 56 glands out of the 134 glands that could have been identified by this technique, failed to identify 75 glands and wrongly localized three glands that
abnormal gland in patients with DGD was 41.8%.
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were found to be normal on surgical exploration. US sensitivity to individually detect an
Fifty five patients had a MIBI. There were 38 true positive glands, 69 false negatives, and
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three falsely identified as abnormal glands. Sensitivity of MIBI to lateralize each individual gland in this group of DGD patients was 34.5%.
4DCT was done in 14 patients. In summary, 4DCT had 18 true positives glands, nine false negatives and one false positive. 4DCT’s sensitivity for each individual gland was 64.3%. On
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Table 3 a summary of imaging outcomes is shown.
Regarding the concordance of paired studies, 54 patients had US and MIBI. From those 54 cases, 27 had two positive results (50%), of which 15 of them agreed on the same side. These 15
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cases reported SGD and were accurate for the gland they described, but missed the second gland. The combination of US plus 4DCT was performed in 14 cases. In seven cases, both US and
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4DCT were positive. However, only one of these agreed on the same location, which was again reported as SGD, correctly lateralizing that parathyroid but missing the second pathologic gland. Thirteen patients had a MIBI and a 4DCT. Both reports were positive in seven cases, of which five agreed in the same side: four reported SGD but one suggested bilateral DGD. They both correctly lateralized six glands and missed four. The percentages of concordance of paired imaging exams were 27.8% for US-MIBI, 7.1% for US-4DCT and 38.5% for MIBI-4DCT. From
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the 68 patients with DGD, 20 had two studies concordant for SGD and only one patient had a correct preoperative diagnosis of DGD by the combination of MIBI and 4DCT. Surgical explorations and IOPTH assay
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From the 504 patients included in the review, 64.3% of the cases (324) consisted of a bilateral neck exploration (BNE), 104 patients (20.6%) underwent a unilateral exploration and 76 (15.1%) a focal exploration. There was a significant difference between the BNE rate in the three groups,
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which was 49.6% for SGD group, 92.6% for DGD group and 100% for MGD group (p<0.001). An IOPTH assay was performed in 94.4% of the cases (93.4% of SGD, 100% of DGD and
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95.3% of MGD; p=0.052). At least one parathyroid tissue sample was sent for intraoperative frozen section in 82.7% of the patients (81.3% of SGD group, 83.8% of DGD and 87.2% of MGD; p=0.44). Parathyroid glands judged as normal by the operating surgeon were not routinely biopsied.
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In the DGD group (n=68), 41 cases (60.3%) had a BNE as initial surgical plan. Seven of these patients (10.3%) had a total thyroidectomy performed at the same surgical procedure. Twenty seven patients (39.7%) had an initial surgical plan of focal exploration. Intraoperative
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measurements of PTH assay were performed in all 68 cases of DGD. In most cases it was performed after the surgical exploration was completed and both abnormal glands had been
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removed, as a confirmation that there was no remaining hyperfunctioning tissue. In 66 patients, the final PTH measurement at the end of the procedure fell greater than 50% from baseline values and into the normal reference range. There were two cases in which, after assessing all four glands and removing the two enlarged ones, PTH did not meet these criteria. In these two cases, the baseline PTH was 62 pg/ml and 77 pg/ml, respectively, and the final PTH fell down into the normal reference values but did not reach a decrease of greater than 50% from baseline
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(31 pg/ml and 52 pg/ml, respectively). Both patients were normocalcemic with normal PTH levels on six months post-operative follow up. There were 24 DGD cases (35.3%) in which the IOPTH assay was carried out after the
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removal of one abnormal gland, and in all of these cases PTH did not drop into the normal range, prompting an extension of the surgical exploration until a second abnormal gland was found. After the removal of the second gland, the PTH did drop appropriately in all 24 cases. Sixty three
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patients (92.6%) in the DGD group ultimately had a BNE. From the 27 planned focal
explorations, 22 were extended to a BNE. In four cases, this change of strategy was due to the
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operative findings, notably the appearance of the initially explored gland(s), leading the surgeon to suspect multi-gland disease. The IOPTH assay results determined the change in surgical approach in the other 18 cases. Therefore, from the 27 cases in which the surgical strategy had to be modified, IOPTH was the driver of an extended exploration in two thirds of these. There were
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only five cases whose surgical procedure was limited to a unilateral exploration. In these, IOPTH assay was performed after finding and removing two abnormal glands and PTH dropped appropriately. Therefore, their exploration was not extended. Figure 1 describes the change of
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surgical strategy that occurred in the various cases. Surgeons’ assessment and surgical pathology
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The median maximum gland diameter and interquartile range of the whole series was 14 mm [10 – 17] and the median gland weight was 383 mg, IQR [200 – 700]. There were significant differences among the three groups in regards to gland size, where SGD group had the largest and heaviest glands and MGD had the smallest and lightest glands (SGD median length of glands: 15 mm, IQR: [12 – 20] vs. DGD median length of glands: 12 mm, IQR: [9 – 15] vs. MGD median length of glands: 10 mm, IQR: [8 – 13]; p<0.001. SGD median weight of glands:
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500 mg, IQR: [269 – 880] vs. DGD median weight of glands: 250 mg, IQR [165 – 507] vs. MGD median weight of glands: 170 mg, IQR: [88 -310], p<0.001). In half of the DGD cases (34 patients) the surgeon stated an asymmetric enlargement of the
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abnormal glands, identifying one gland as the “dominant” adenoma. In the remaining cases, the surgeon did not report a major difference in the sizes of the two excised glands. The DGD cases were divided into 2 categories: symmetric and asymmetric. The pathologic data confirmed the
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surgeons’ observations: the “asymmetric adenoma 1” were significantly heavier and larger than the “asymmetric adenoma 2” (p=0.014) and no differences were found between “symmetric
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adenoma 1” compared to “symmetric adenoma 2” (p=0.151, results not shown in table). When comparing the weights and sizes of the symmetric versus the asymmetric enlarged glands, we found a significant difference (p=0.025) in the length of “adenoma 1” in the asymmetric group but not on the glandular weight (p=0.113) compared to “adenoma 1” in the symmetric group.
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There was also no statistical significant difference among the adenoma 2 in the symmetric and asymmetric groups (see Table 4). The presence of a “dominant” gland assessed by the surgeons in the asymmetric group matched what the pathologist measured. Nonetheless, the smallest gland
Surgical outcomes
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in the asymmetric group was not different from any of the glands in the symmetric group.
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The median follow up of the complete series was 26.1 months (IQR [13.7 – 38]). The latest postoperative biochemical values revealed a median serum calcium of 9.5 mg/dL, IQR: [9.2 – 9.8]; median serum ionized calcium: 1.23 mmol/dL, IQR: [1.18 – 1.27]; median serum PTH: 45 pg/mL, IQR: [34 – 58.2]; median serum phosphorus: 3.1 mg/dL, IQR: [2.7 – 3.5]; median serum 25-hydroxy vitamin D3: 36 ng/mL, IQR: [29 – 45]; and median serum creatinine: 0.85 mg/dL, IQR: [0.71 – 1.02]. There were no differences between the postoperative biochemical values
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among the three groups, except for the serum creatinine, which was slightly higher in the MGD group compared to the SGD group (SGD: 0.83 mg/dl, IQR: [0.7 – 1] vs. MGD: 0.88 mg/dL, IQR: [0.76 – 1.18]; p=0.02).
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The cure rate after surgery was 95%. The MGD group had a significantly lower cure rate compared to the other two groups (SGD: 96.8% vs. DGD group: 100% vs. MGD: 83.7%;
p<0.001). The difference in cure rate between SGD and DGD was not statistically significant
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(p=0.22). One hundred one patients (20.2%) had a persistently elevated serum PTH with normal serum calcium postoperatively. The percentages of postoperative normocalcemic HPT did not
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differ significantly among the three groups (SGD: 18.7% vs. DGD: 22.1% vs. MGD: 24.4%; p=0.434). Two of these patients (both SGD) were found to have a recurrence of disease after an apparently curative BNE with one gland removed.
After at least six months of follow up, all DGD patients remained eucalcemic with a median
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serum calcium of 9.6 mg/dl (IQR [9.2 – 9.9]) and median serum PTH of 44 pg/mL (IQR [33 – 58]). There were 15 DGD patients with elevated postoperative PTH levels and calcium levels well within the normal range. For these 15 patients, the median PTH was 70 pg/mL (IQR [51 –
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85]) and median postoperative calcium was 9.6 mg/dL (IQR [9.4 -9.8]). Three of these patients had mild chronic kidney disease.
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In the whole series, 35 patients (6.9%) presented with postoperative hypocalcemia. There were no differences in the hypocalcemia rates between the surgical approaches (BNE, unilateral neck exploration). Of these 35 patients, four of them were still dependant on oral calcium supplements six months after surgery (permanent hypocalcemia of 0.8%). However, the MGD group had the highest percentage of postoperative hypocalcemia (SGD: 5.8% vs. DGD: 2.9% vs. MGD: 15.1%; p=0.007). There was one case (0.2%) of neck hematoma that required emergent
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re-operation for evacuation. This patient had SGD but a concurrent total thyroidectomy. Another case (0.2%) was complicated by a transient unilateral vocal cord paralysis that fully recovered three months post-operatively.
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DISCUSSION
In our opinion, “double adenoma” is a real clinical entity that can result in difficult operative situations and failed explorations. Although relatively uncommon compared to single gland
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disease, it should be considered in patients undergoing surgery for primary hyperparathyroidism. This is evidenced in our series of patients with two removed glands and surgical cure with a
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considerable length of post-operative follow up (median of 26 months), during which time we are able to say that so far the 68 patients with DGD in our series have not presented with recurrence or persistence of disease. As Milas and colleagues 4 described in their study, during the past decades there has been an increase in the reported incidence of double adenoma, which
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is likely attributable to the greater awareness of this entity by surgeons and the widespread use of IOPTH during cervical explorations. In our series we found a higher incidence of double adenoma than most authors (13.5%), 3,6,8,10,12,14,17,18 but similar to that reported in more recent
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studies. 4,7,15
Most groups have found that a bilateral distribution of the two adenomas is more common
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than unilateral. 3,4,6,12,15-17 In our case, we found that almost 65% of the cases followed this pattern. We did not find any differences in regard to gender distribution. Kandil 6 found that double adenoma was proportionally more common in men, while Szabo 15 observed a greater proportion of female patients in their SGD group compared to the percentage of females with double or multi-gland disease. Regarding age, we found that patients with a final diagnosis of MGD were older than patients with SGD and DGD. In contrast, another study found that DGD
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was associated with older age. 16 In a different publication by the same group, an association was found between older age and recurrence or persistence of HPT due to DGD, compared to recurrence or persistence due to MGD. 19
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Many studies have documented that localization studies are generally inaccurate in cases of multi-gland disease. 4,12,16,20 Haciyanli 3 published the most optimistic study regarding the
combined results of US, MIBI and IOPTH in patients with double adenoma. They found that
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80% of the cases had a diagnosis of double adenoma by at least one of the tests, US or MIBI or IOPTH. We observed that it was uncommon for any imaging modality to simultaneously and
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accurately lateralize both abnormal glands. There was only one case where MIBI and 4DCT were concordant for the same two glands. However, the high rates of negative, inconclusive or discordant tests resulted in a positive outcome for patients with DGD, since these poorly defined pre-operative imaging reports drove the decision towards a BNE. The real challenge came for
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those DGD patients who had conclusive and even concordant studies indicating SGD. It was in these patients where IOPTH played a crucial role guiding the surgeons until they had resected all hyperfunctioning glands. In our series, approximately 40% of the DGD patients fell into this
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risky group and IOPTH “saved” them from an unsuccessful parathyroidectomy. Our experience with the use of IOPTH was excellent and better than what other authors have reported, 3,4,6,7,14,20
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as in no case did it drop until both adenomas had been removed. Similarly to what Milas and colleagues did in their study, 4 we divided our DGD patients depending on the symmetry of the two enlarged glands. The asymmetry between the two glands assessed by the surgeons was supported by the differences in weight and maximum diameter measured by the pathologists. In general terms, we could say that half of the patients had two similarly enlarged glands and the other half had a larger gland accompanied by a smaller but still
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abnormal gland. Although we did not look specifically at which of the glands was removed first (largest or smallest), in no case, independent of which subgroup the patient belonged to, did the IOPTH fall until both abnormal glands had been removed. In Milas’ study, the authors observed
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a greater percentage of false positive IOPTH drop in cases of asymmetric enlargement where the largest gland had been removed first, not predicting the presence of a second enlarged gland. 4 In our series, only 35% of DGD cases had an IOPTH assay after one first gland had been removed.
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It is possible that we would have found more false positive results in the IOPTH assay if we had performed the test before the resection of the second abnormal gland more often.
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There are some limitations to our study. First we must acknowledge its retrospective nature, as well as the variation in surgical practices and operative report dictation among the seven surgeons who contributed in this series. Fortunately, the majority of the operative reports were formatted in a standardized fashion. A summary of the patients’ history and the initial surgical
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plan was clearly reflected in the opening paragraph. With regards to the surgeons’ approach to normal-appearing glands, most were inspected and determined to be normal based on the size, color, and texture of the gland. Only in rare circumstances were normal glands biopsied. There
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were 14 cases of SGD were a second gland was entirely removed, based on the initial assessment of the glands’ appearance, but after removal the surgeon clearly stated in the operative report that
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the gland appeared normal and this was corroborated by the intraoperative frozen section. Most surgeons described each explored gland in the operative report and explained how their decisions were or were not influenced by the IOPTH assay or the results of the intraoperative frozen section. In addition to this, not all DGD had a BNE. Five patients had a unilateral exploration followed by an IOPTH drop after the removal of two enlarged glands. In these cases the surgeon decided not to extend the exploration. These patients remain eucalcemic. Nevertheless, we
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acknowledge that a BNE in the setting of two unilateral enlarged glands would have been the ideal course of action to ensure that the contralateral glands were normal. Another limitation of our study is that we restricted our analyzed patient population only to
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those with well-documented six months follow up laboratory values. This excluded almost half of the patients who underwent parathyroidectomy during the study time period. However, given the importance of the documentation of biochemical cure, we thought this was most appropriate.
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An additional issue that merits comment is that there were 101 patients (20.2%) with persistent post-operative elevation of serum PTH. Two of these patients have a documented recurrence,
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both of which had a single gland removed at the initial operation. Patients with an elevated PTH and normocalcemia after parathyroid surgery could have vitamin D deficiency, persistent pHPT with normocalcemia, or relative post-operative hypocalcemia with a need for additional calcium supplementation. More rigorous follow up of these patients would clearly be of benefit to better
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define the cause of the elevated PTH and treat accordingly.
The debate about the definition of parathyroid adenoma, hyperplasia and the existence of multiple adenomas has been ongoing for decades. 8,9,21,22 There is still no consensus about the
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pathological differentiating characteristics between adenomatous or hyperplasic parathyroid glands. 9,11,23 Despite the various techniques used by pathologists to try to determine the nature
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of a pathologic parathyroid gland, this distinction is difficult to define. 13,23-25 Adenomas are believed to be a monoclonal proliferation while hyperplasia is considered a polyclonal overgrowth of parathyroid tissue. However, monoclonality has been also observed in hyperplastic glands. 26,27 Cetani and colleagues 28 studied seven families with isolated familial HPT (with no other MEN associated conditions) and found MEN1 mutations in three of them and all of these were found to have MGD. Dwight 29 focused her analysis on five patients with
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double adenoma and observed different genetic changes in the two tumors of each patient, suggesting independent somatic mutations were the cause of multiple parathyroid tumors. 30% of these tumors had MEN1 loss of heterozigosity but these mutations were not present in all
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tumors within the same patient. As plausible explanations for these findings, the authors suggested the occurrence of different primary genetic events or the possibility that other
unknown factors could prompt several tumorigenic events in the same individual. 29 All these
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discoveries are promising and may help clarify the underlying pathogenesis of parathyroid
tumors. While this histological issue remains unsolved, it may be time to consider a change in
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nomenclature. As other authors have suggested, 15 we preferred to use the terms single, double or multi-gland disease in our analysis, independently of how the pathologist had described the specimens.
In summary, surgeons must be aware that up to a third of their patients could have two or
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more abnormal glands, even with preoperative imaging indicating SGD. In our experience, there is a considerable percentage of patients in which two abnormal glands are discovered during surgery and cure is achieved after resecting the enlarged glands. IOPTH has proven to be
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accurate in predicting postoperative normocalcemia. However, the experience of some groups with IOPTH in the presence of two or more enlarged glands raises the question of the
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significance of each gland in the hypersecretion of PTH. In treating and operating on patients with pHPT, surgeons must assemble the relevant pre-operative clinical information, localization studies, intra-operative findings and IOPTH results, in ultimately deciding the extent of operation and the removal of individual parathyroid glands. Until the insights of parathyroid enlargement and overproduction are better understood, surgeons must use their experience, judgment and skills in determining the best course of action in each individual patient.
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REFERENCES 1. Consensus development conference statement. J Bone Miner Res 1991;6:S9-13. 2. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic
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primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab 2014;99:3561-3569.
3. Haciyanli M, Lal G, Morita E, et al. Accuracy of preoperative localization studies and
double adenoma. J Am Coll Surg 2003;197:739-746.
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intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and
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4. Milas M, Wagner K, Easley KA, et al. Double adenomas revisited: Nonuniform distribution favors enlarged superior parathyroids (fourth pouch disease). Surgery 2003;134:995-1003; discussion 1003-1004.
5. Molinari AS, Irvin GL 3rd, Deriso GT, Bott L. Incidence of multiglandular disease in primary
discussion 936-937.
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hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996;120:934-936;
6. Kandil E, Alabbas HH, Bansal A, et al. Intraoperative parathyroid hormone assay in patients
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with primary hyperparathyroidism and double adenoma. Arch Otolaryngol Head Neck Surg 2009;135:1206-1208.
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7. Gordon LL, Snyder WH 3rd, Wians F Jr, et al. The validity of quick intraoperative parathyroid hormone assay: An evaluation in seventy-two patients based on gross morphologic criteria. Surgery 1999;126:1030-1035. 8. Wang CA, Rieder SV. A density test for the intraoperative differentiation of parathyroid hyperplasia from neoplasia. Ann Surg 1978;187:63-67.
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9. Ghandur-Mnaymneh L, Kimura N. The parathyroid adenoma. A histopathologic definition with a study of 172 cases of primary hyperparathyroidism. Am J Pathol 1984;115:70-83. 10. Attie JN, Bock G, Auguste LJ. Multiple parathyroid adenomas: Report of thirty-three cases.
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Surgery 1990;108:1014-1019; discussion 1019-1020.
11. Baloch ZW, LiVolsi VA. Double adenoma of the parathyroid gland: Does the entity exist? Arch Pathol Lab Med 2001;125:178-179.
double adenomas. J Am Coll Surg 2004;198:185-189.
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12. Bergson EJ, Heller KS. The clinical significance and anatomic distribution of parathyroid
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13. Bonjer HJ, Bruining HA, Birkenhager JC, et al. Single and multigland disease in primary hyperparathyroidism: Clinical follow-up, histopathology, and flow cytometric DNA analysis. World J Surg 1992;16:737-743; discussion 743-744.
14. Gauger PG, Agarwal G, England BG, et al. Intraoperative parathyroid hormone monitoring
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fails to detect double parathyroid adenomas: A 2-institution experience. Surgery 2001;130:10051010.
15. Szabo E, Lundgren E, Juhlin C, et al. Double parathyroid adenoma, a clinically nondistinct
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entity of primary hyperparathyroidism. World J Surg 1998;22:708-713. 16. Tezelman S, Shen W, Shaver JK, et al. Double parathyroid adenomas. clinical and
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biochemical characteristics before and after parathyroidectomy. Ann Surg 1993;218:300-307discussion 307-309.
17. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995;82:926-929. 18. van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: An institutional perspective. World J Surg 1991;15:688-692.
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19. Tezelman S, Shen W, Siperstein AE, et al. Persistent or recurrent hyperparathyroidism in patients with double adenomas. Surgery 1995;118:1115-1122. 20. Genc H, Morita E, Perrier ND, et al. Differing histologic findings after bilateral and focused
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parathyroidectomy. J Am Coll Surg 2003;196:535-540.
21. Harness JK, Ramsburg SR, Nishiyama RH, Thompson NW. Multiple adenomas of the parathyroids: Do they exist? Arch Surg 1979;114:468-474.
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22. Cope O. Endocrine surgery. Surg Clin North Am 1978;58:957-966.
23. Grimelius L, Akerstrom G, Bondeson L, et al. The role of the pathologist in diagnosis and
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surgical decision making in hyperparathyroidism. World J Surg 1991;15:698-705. 24. Roth SI, Gallagher MJ. The rapid identification of "normal" parathyroid glands by the presence of intracellular fat. Am J Pathol 1976;84:521-528.
25. Yao K, Singer FR, Roth SI, et al. Weight of normal parathyroid glands in patients with
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parathyroid adenomas. J Clin Endocrinol Metab 2004;89:3208-3213. 26. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658-662.
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27. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995;95:2047-2053.
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28. Cetani F, Pardi E, Ambrogini E, et al. Genetic analyses in familial isolated hyperparathyroidism: Implication for clinical assessment and surgical management. Clin Endocrinol (Oxf) 2006;64:146-152. 29. Dwight T, Nelson AE, Theodosopoulos G, et al. Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism. Am J Pathol 2002;161:1299-1306.
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Table 1. General Description of the Series and Comparison Between Single Gland, Double Gland, and Multi-Gland Disease Groups SGD 347 68.9% 59.9 ± 12.6 268 77.2% 28.8 ± 6.5 14 4.0%
DGD 68 13.5% 60.6 ± 12.2 56 82.4% 28.5 ± 6.1 3 4.4%
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DGD, double gland; HPT, hyperparathyroidism; MGD, multi-gland; SGD, single gland.
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MGD 86 17.1% 63.9 ± 9.9 73 84.9% 27.8 ± 5.5 8 9.3%
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Total 504 60.6 ± 12.3 397 79.2% 28.6 ± 6.3 25 5%
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n, % Age, y, mean ± SD Female, n, % BMI, kg/m2, mean ± SD Familial history of HPT, n, % *Statistical significance.
p Value 0.023* 0.248 0.446 0.144
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Table 2. Three Group Comparison of Preoperative Biochemical Values SGD
DGD
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Total
MGD
p Value
IQR
Median
IQR
Median
IQR
Median
IQR
Serum calcium, mg/dL
10.9
[10.6 - 11.4]
11
[10.6 - 11.5]
10.9
[10.6 - 11.4]
10.7
[10.4 - 11.1]
<0.001*
Serum ionized calcium, nmol/dL
1.4
[1.35 - 1.46]
1.4
[1.35 - 1.47]
1.4
[1.35 - 1.49]
1.36
[1.32 - 1.44]
0.007*
Serum parathyroidism, pg/mL
101
[76.25 - 131]
104
[78 - 135.5]
97.5
[73.2 - 124.2]
93
[72.5 - 124.5]
0.080
Serum phosphorus, mg/dL
2.6
[2.2 - 3]
2.6
Serum vitamin D, ng/mL
35
[27 - 42]
34
Serum creatinine, mg/dL
0.84
[0.73 - 1]
0.82
24-h Urine calcium, mg
273.5
[162.2 - 369.7]
300
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2.7
[2.3 - 2.9]
2.8
[2.5 - 3.1]
<0.001*
[26 - 42]
33
[26 - 41]
39
[32 - 45.7]
0.004*
[0.71 - 0.94]
0.9
[0.76 - 1.02]
0.9
[0.76 - 1.15]
0.002*
[179.5 - 390]
228
[161 - 336]
171.5
[115.5 - 321.5]
0.001*
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*Statistical significance.
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Median
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DGD, double gland; IQR, interquartile range; MGD, multi-gland; SGD, single gland.
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Table 3. Results of Imaging Studies in Patients with Double-Gland Disease %
True positives
False negatives
False positives Sensitivity, %
US
67
98.5
56
75
3
41.8
MIBI
55
80.9
38
69
3
34.5
4DCT
14
20.6
18
9
1
64.3
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US, Ultrasound; MIBI, 99mTechnethium-Sestamibi SPECT; 4DCT, 4-dimension CT.
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n
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Table 4. Comparison between Symmetric and Asymmetric Enlarged Adenomas Resected from the Double Gland Disease Patients
Median
IQR
Asymmetric enlargement Median
Adenoma 1 254.5
[140 - 625]
370
[265 - 584]
0.113
Length, mm
11
[10 - 15]
15
[11.5 - 19]
0.025*
Weight, mg
194
[109 - 300]
110
[81.5 - 232]
0.134
Length, mm
11
[8 - 15]
[7.5 - 14]
0.345
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*Statistical significance.
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IQR, interquartile range.
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Weight, mg
Adenoma 2
25
IQR
p Value
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Symmetric enlargement
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Figure Legend Figure 1. Diagram showing the procedure flow of the double-gland disease patients. All 68 patients had 2 abnormal glands removed at surgical exploration. BNE, bilateral neck exploration; IoPTH,
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intraoperative parathyroid hormone assay; PTH, parathyroid hormone.
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Precis Retrospective review of a series of cases operated on for primary hyperparathyroidism and analysis of the incidence and outcomes of patients with two abnormal glands resected
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and the intra-operative parathyroid hormone assay in this setting.
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during surgery. Particular attention is dedicated to the role of preoperative imaging studies
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Figure 1.