Multiphase computed tomography for localization of parathyroid disease in patients with primary hyperparathyroidism: How many phases do we really need? Salem I. Noureldine, MD,a Nafi Aygun, MD,b Michael J. Walden, MD,b Ahmed Hassoon, MD, MPH,c Sachin K. Gujar, MD,b and Ralph P. Tufano, MD, MBA, FACS,a Baltimore, MD

Background. Multiphase computed tomography (CT) involves multiple cervical CT acquisitions to accurately identify hyperfunctional parathyroid glands, thus increasing radiation exposure to the patient. We hypothesized that only 2 cervical acquisitions, instead of the conventional 4, would provide equivalent localization information and halve the radiation exposure. Methods. We identified 53 consecutive patients with primary hyperparathyroidism who underwent multiphase CT before parathyroidectomy. All scans were reinterpreted first using 2 phases then using all 4 phases. The accuracies of interpretations were determined with surgical findings serving as the standard of reference. Results. Sixty-four hyperfunctional parathyroid glands were resected with a mean weight of 394.3 mg. Twophase CT lateralized the hyperfunctional glands in 38 patients with a sensitivity, positive predictive value (PPV), and accuracy of 100%, 71.7%, and 71.7%, respectively. Four-phase CT lateralized the hyperfunctional glands in 39 patients with a sensitivity, PPV, and accuracy of 95.1%, 76.5%, and 73.6%, respectively. For quadrant localization, the accuracy of 2-phase and 4-phase CT was 50.9% and 52.8%, respectively. Conclusion. Our results suggest that 2-phase and 4-phase CT provide an equivalent diagnostic accuracy in localizing hyperfunctional parathyroid glands. The reduced radiation exposure to the patient may make 2-phase acquisitions a more acceptable alternative for preoperative localization. (Surgery 2014;156:1300-7.) From the Division of Head and Neck Endocrine Surgery, Department of Otolaryngology – Head and Neck Surgery,a the Department of Radiology and Radiological Science,b Johns Hopkins University School of Medicine, and the Department of Epidemiology,c Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

HIGH-QUALITY PREOPERATIVE IMAGING is a critical component for the success of targeted parathyroidectomy in patients with primary hyperparathyroidism Presented at the American Association of Endocrine Surgeons 2014 annual meeting, April 28, 2014, Boston, Massachusetts. S.I.N. and N.A. contributed equally to this work. Financial Disclosure: The authors have no financial interests in companies or other entities that have an interest in the information included in the contribution. Conflicts of Interest: All authors report no conflicts of interest. Accepted for publication August 7, 2014. Reprint requests: Ralph P. Tufano, MD, MBA, FACS, Charles W. Cummings MD Professor, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine, Johns Hopkins Outpatient Center; 601 N. Caroline Street, 6th floor Baltimore, MD 21287. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.


(PHPT). Currently, the majority of institutions use ultrasonography (US) and technetium-99m (Tc99m) sestamibi scanning for preoperative localization, with reported sensitivities of 50–85% and 60–92%, respectively, when deployed individually. There is a reported increase in the likelihood of successful localization of hyperfunctional parathyroid glands when US and Tc-99m sestamibi are used in combination (73-95%).1-6 Shortcomings of this approach include the inability to screen the mediastinum with US, limited spatial resolution of Tc-99m sestamibi, operator dependability, and lack of anatomic landmarks identifiable on these types of images that would help the surgeon to approach parathyroidectomy in a focused or targeted manner.7 The addition of single photon emission computed tomography (CT) and conventional CT has allowed some improvements in these limitations.1

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Recent studies suggest that multiphase CT, also known as 4-dimensional CT in the parathyroid imaging lexicon, has a higher sensitivity and accuracy for preoperative localization of hyperfunctional parathyroid glands in patients with PHPT than either Tc-99m sestamibi scanning, US, or both combined.1,7-10 Multiphase CT involves 4 sequential CT acquisitions through the neck once before administration of intravenous contrast material and 3 additional predetermined times after contrast is given. These separate CT acquisitions are variably referred to as precontrast, arterial, venous, and delayed phases. Multiphase CT permits visualization of tissue at 4 successive time points as the contrast bolus is passing through, which provides information about how fast and how high the contrast enhancement of various tissue is, as well as, how quickly the contrast material washes out. Because parathyroid glands exhibit different contrast enhancement and washout characteristics than lymph nodes and vessels, differentiation of hyperfunctional parathyroid glands from mimickers can be achieved.11 Multiphase CT has become a favored imaging modality, particularly for reoperative parathyroid surgery or when other preoperative imaging modalities fail to localize a hyperfunctional parathyroid gland.1,9-12 However, the main drawback of multiphase CT is its high radiation dose, with a conservative dose estimate of 27 millisievert (mSv) for a typical multiphase CT examination with 4 phases compared with 11 mSv for a Tc-99m sestamibi scan.9 Twenty-seven mSv is equivalent to the radiation dose that an average American receives from natural background radiation over 9 years.8,13 Beland et al11 have shown that hyperfunctional parathyroid glands often show rapid enhancement and early washout. Therefore, the delayed phase could be eliminated because there is no significant difference in the enhancement characteristics of lymph nodes and hyperfunctional parathyroid glands in this phase. The change from a 4-phase to a 3-phase CT protocol allowed reduction in the effective radiation dose of a multiphase CT to 21 mSv.14 We hypothesized that elimination of the precontrast and delayed phases from the typical 4-phase acquisition would not result in diminished diagnostic accuracy while halving the radiation exposure. MATERIALS AND METHODS Data source. Data were extracted from the medical record reports of all consecutive patients

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with biochemically confirmed PHPT (calcium level >10.4 mg/dL and/or serum intact parathyroid hormone [iPTH] level >65 pg/mL) who underwent multiphase CT for preoperative localization before undergoing primary parathyroidectomy. All multiphase CT scans were performed at our institution between September 2008 and May 2013 and interpreted by a single, board-certified neuroradiologist. All primary parathyroidectomy procedures were performed by a single highvolume surgeon at our institution between September 2008 and September 2013. Multiphase CT studies were obtained to assist in localizing hyperfunctional parathyroid glands in surgeryna€ıve patients with nonlocalizing or discordant US and sestamibi imaging, who otherwise were deemed possible candidates for targeted primary parathyroidectomy. The surgical notes were reviewed without knowledge of the 2-phase and 4phase CT readings, and the site and weight of the resected hyperfunctional parathyroid glands were recorded. This retrospective study was approved by the Institutional Review Board of Johns Hopkins Medicine, and informed consent was waived in accordance with the Health Insurance Portability and Accountability Act. Multiphase CT image processing. Imaging was performed using a Siemens (Erlangen, Germany) Somatom Definition 64 CT scanner in helical mode set from 2 cm below the carina to the skull base. The scanning parameters were 120 kVp with an effective tube current of approximately 220 mA and pitch of 0.75. Nonoverlapping 0.75 3 3.0-mm axial reconstructions were created in each of the 4 phases along with sagittal, coronal, and 2 oblique reformatted images. The first phase was without intravenous iodinated contrast and consisted of an initial unenhanced scan (precontrast phase). Twenty-five seconds before the beginning of the second phase, intravenous contrast administration of 120 mL of nonionic contrast material (Iohexol [Omnipaque 350; GE Healthcare, Little Chalfont, Buckinghamshire, United Kingdom] or Iodixanol [Visipaque 320; GE Healthcare,]) was begun at 3 mL/s (arterial phase). This timing was chosen such that imaging through the neck occurred during maximal arterial opacification. Sixty-eight seconds after the end of the second phase, the third phase (venous phase) commenced and 111 seconds after the end of the third phase, the final acquisition (delayed phase) began (Figure). The calculated mean volume CT dose index as required by the state regulatory body was recorded as the radiation absorbed dose.

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Figure. Multiphase computed tomography (CT) of a patient with primary hyperparathyroidism. No lesions were identified on ultrasound or Tc-99m sestamibi. Multiphase CT demonstrates an avidly enhancing lesion (arrows) posterior to the left thyroid inferiorly with marked enhancement in the arterial phase and rapid washout of contrast in the venous phase. (A) Precontrast phase. (B) Arterial phase. (C) Venous phase. (D) Delayed phase.

Reinterpretation of multiphase CT acquisitions. Interpretation of the multiphase CT acquisitions was performed between December 2011 and November 2013. All patient-identifying information was removed from the images by a medical student who was not involved in other aspects of the study. The precontrast (phase I) and delayed (phase 4) acquisitions were extracted from the complete data sets, anonymized, and saved with unique identifiers. The remaining 2-phase datasets that included the arterial (phase 2) and venous (phase 3) phases were presented in a random fashion for interpretation. A board-certified neuroradiologist, with 10 years of post-training experience in reading head and neck CTs, independently reviewed all studies using a commercially available picture archiving and communication system (Ultravisual, Emageon, Madison, WI). The reviewer had the capability of creating multiplanar reformats and measuring attenuation coefficients as deemed necessary. The radiologist was blinded to the surgical outcomes and all clinical data, except that the subjects had PHPT with nonlocalizing or discordant US and Tc-99m sestamibi imaging results, which in our practice prompts the acquisition of a multiphase CT scan. Suspected hyperfunctional parathyroid glands were recorded with corresponding table locations. The reviewer assigned a confidence level of 1, 2, or 3 to his readings based on the location, appearance, and enhancement characteristics of the

hyperfunctional glands: 1, very confident; 3, not confident; and 2 when there was confidence in the reading, but not as strong as 1. After a period of >3 months, anonymized image sets that included all 4 phases of the CT examinations were presented to the same neuroradiologist in a random fashion and with unique identifiers that did not permit establishing a connection with the previous 2-phase CT interpretations. The locations of the suspected hyperfunctional parathyroid glands and the confidence levels for each case were recorded in a similar fashion. As per our practice, all outside Tc-99m sestamibi scans were reinterpreted preoperatively at our institution. We did not reinterpret any of the US imaging studies. The results of both imaging tests were obtained from the review of medical records. Standard of reference. The suspected locations of the hyperfunctional parathyroid glands were correlated with the surgical reports, pathology reports, and intraoperative rapid parathyroid hormone assays for each patient to determine the accuracy of each interpretation for both the 4phase and 2-phase data sets independently. Intraoperative biochemical resolution of PHPT was defined as a 50% drop from baseline and into the normal range. Because all patients had biochemical confirmation of PHPT as a condition of inclusion, the sensitivity, positive predictive value (PPV), and accuracy of the preoperative imaging tests were

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only calculated. A true positive was defined as the probability that the tests correctly identified the hyperfunctional parathyroid gland in cases of single adenomas or correctly identified the location of all hyperfunctional glands in patients with multigland disease. PPV was defined as the probability that a patient with positive test had a single hyperfunctional parathyroid gland or multigland disease. A false positive (FP) was defined as tests that incorrectly suggested lateralization of a hyperfunctional parathyroid gland or the presence of multigland disease, and a false negative was defined as tests incorrectly suggested the absence of hyperfunctional parathyroid glands. Lateralization accuracy was determined as the number of patients in whom the imaging study correctly identified the anatomic side of the hyperfunctional parathyroid gland. The accuracy of quadrant localization was defined as the number of patients in whom each imaging technique correctly identified all the quadrant anatomic locations (right/ left, superior/inferior) of the hyperfunctional parathyroid glands, expressed as a percentage of the total number of patients in the study. We utilized the surgical anatomic location of the identified hyperfunctional parathyroid gland for accurate quadrant localization rather than the actual embryonic origin. We believe that the anatomic location is more helpful to the surgeon in pursuing a focused or targeted parathyroidectomy (eg, superior parathyroid adenoma that has migrated caudally to lie in the inferior quadrant with respect to the thyroid lobe). Statistical analysis. Data analysis was performed using STATA version 13 (StataCorp, College Station, TX). Sensitivity, PPV, and accuracy were calculated relative to surgical findings. All values are expressed as means ± standard deviation, ranges, or absolute numbers unless specified otherwise. RESULTS A total of 53 patients were identified during the study period; 37 (69.8%) were women and 16 (30.2%) were men with a mean age at admission of 56.9 ± 11.4 years (range, 31–78). The mean preoperative serum calcium and iPTH levels were 11 ± 0.6 mg/dL (median, 11) and 95.7 ± 58.2 pg/mL (median, 82.4), respectively. Sixty-four hyperfunctional parathyroid glands were resected during surgery with a mean weight and volume of 394.3 ± 301.1 mg (median, 300) and 465.4 ± 294.1 mm3 (median, 410), respectively. At surgery, 42 patients in the study cohort (79.2%) had a single, hyperfunctional parathyroid gland.

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In the remaining 11 patients (20.8%), 2 hyperfunctional parathyroid glands were found. Overall, there were 14 left superior, 13 left inferior, 15 right superior, 19 right inferior, and 3 mediastinal parathyroid glands resected. US was used in all patients and Tc-99m sestamibi was used in 52 patients (98.1%) during their initial preoperative evaluation. Only 38 US (71.7%) and 42 sestamibi (80.8%) scans were performed at our institution. The remaining were requested by a referring physician from an outside institution and were not repeated at our institution. Preoperatively, all US and Tc-99m sestamibi studies were either nonlocalizing or discordant. The sensitivity, PPV, and accuracy of US was 57.1%, 52.6%, and 37.7%, respectively. The sensitivity, PPV, and accuracy of Tc-99m sestamibi imaging was 48.7%, 59.4%, and 36.5%, respectively. When combined, the sensitivity, PPV, and accuracy were 82.9%, 63.0%, and 55.8%, respectively. US and sestamibi correctly coincided in lateralizing all hyperfunctional parathyroid glands in only 9 patients (17.3%). Table I summarizes the sensitivity, PPV, and accuracy of all 4 imaging modalities in detecting the hyperfunctional parathyroid glands. Overall, 2-phase CT identified 70 potential hyperfunctional parathyroid glands and achieved a lateralization accuracy of 71.7%. Two-phase CT achieved a localization accuracy of 50.9% in correctly identifying the anatomic quadrant of all hyperfunctional parathyroid glands in 27 of the 53 patients. Four-phase CT identified 67 potential hyperfunctional parathyroid glands and achieved a lateralization accuracy of 73.6%. Four-phase CT achieved a localization accuracy of 52.8% in correctly identifying the anatomic quadrant of all hyperfunctional parathyroid glands in 28 of the 53 patients. The mean volume CT dose index for 4-phase and 2-phase CT were 63.6 mGy and 31.8 mGy, respectively. All hyperfunctional parathyroid glands identified on 2-phase and 4-phase CT were assigned a confidence level. Table II summarizes the outcome of identified hyperfunctional glands per confidence level. Of the 12 patients with FP interpretations on 4-phase CT, 50% were found to have multigland disease. In this group, the mean preoperative serum iPTH and calcium levels were 72.7 ± 31.0 pg/mL and 10.8 ± 0.7 mg/dL, respectively, and 66% of the patients had an iPTH level of

Multiphase computed tomography for localization of parathyroid disease in patients with primary hyperparathyroidism: How many phases do we really need?

Multiphase computed tomography (CT) involves multiple cervical CT acquisitions to accurately identify hyperfunctional parathyroid glands, thus increas...
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