Use of surgeon-performed office ultrasound and parathyroid fine needle aspiration for complex parathyroid localization

Use of surgeon-performed office ultrasound and parathyroid fine needle aspiration for complex parathyroid localization Antonia E. Stephen, MD,a Mira Milas, MD,b Carolyn N. Garner, MD,b Kristen E. Wagner, MD,b and Allan E. Siperstein, MD,b Boston, MA, and Cleveland, OH

Background. This study investigates the utility of ultrasound guided parathyroid fine needle aspiration (FNA) as a localizing technique in patients with hyperparathyroidism (HPT) undergoing re-operative neck surgery or with unusually appearing or ectopically located glands. Methods. Selected patients with HPT underwent surgeon-performed FNA with ultrasound guidance. Aspirate contents were sent for cytology and parathyroid hormone (PTH) levels. All patients subsequently underwent parathyroid exploration. Results. 54 patients underwent 57 ultrasound guided parathyroid biopsies. Indications for FNA included prior parathyroid (n = 29), thyroid (n = 11), or other neck surgery (n = 2), or unusual parathyroid appearance or location (n = 12). A true positive was defined as a site where the PTH aspirate was >40 pg/mL and a hypercellular gland was removed at surgery. Based on this, there were 44 true positives, 10 true negatives, and 3 false negatives; there were no false positives. The median PTH level in positive aspirates was 11,665 pg/mL. Cytology was primarily helpful in excluding other diagnoses. Conclusion. Ultrasound guided FNA is a highly specific localization test for parathyroid tumors. This procedure can be successfully performed by surgeons in the office setting and is extremely valuable for directing parathyroid exploration in challenging cases. We recommend incorporating ultrasound and FNA as a pre-operative localization strategy for selected patients with HPT. (Surgery 2005;138:1143-51.) From the Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA,a and Department of Surgery, Cleveland Clinic Foundation, Cleveland, OH b

It is well documented that bilateral, four-gland explorations for patients presenting with primary hyperparathyroidism (HPT) for an initial operation have a success rate of greater than 95% when the surgery is performed by an experienced parathyroid surgeon.1,2 Recent literature supports the claim of similar success rates for focal explorations using pre-operative localization and intra-operative parathyroid hormone (PTH) measurement.3,4 Despite these excellent results, there remains a small but significant number of patients for whom safe and successful parathyroid surgery is considerably more challenging. This group includes patients with persistent or recurrent HPT, those who have Reprint requests: Antonia E. Stephen, Division of Surgical Oncology Massachusetts General Hospital 55 Fruit Street Boston, MA 02114 Office phone: 617726-0531 Office fax: 617 724-3895. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2005.08.030

had previous thyroid surgery, or those with glands located in ectopic locations. In addition, patients with renal failure resulting in secondary or tertiary HPT, as well as those with familial parathyroid disease, are at increased risk of recurrence. Although many surgeons obtain pre-operative localization studies prior to initial parathyroid surgery, most would agree that absolute identification of the abnormal gland(s) is not required prior to initial surgery when 4-gland exploration is planned. This is not the case for re-operative parathyroid surgery, where localization studies are often used to direct a focal exploration. The success rate for reoperative parathyroid surgery is estimated to be approximately 60% without pre-operative localization; this increases to 89% when pre-operative localization studies are obtained and a standard approach is to require at least two concordant localization procedures prior to re-exploration.5,6 Localization studies for patients undergoing re-operative parathyroid surgery include technetium-99 sestamibi scan, neck ultrasound, magnetic SURGERY 1143

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resonance imaging (MRI), computed tomography (CT) scan, selective venous sampling, and angiography. Each of these localization procedures have variable sensitivity and specificity reported in the literature,7-9 and some are expensive, invasive, and time-consuming for the patient. In recent years, the technology of high-resolution ultrasound has markedly improved and in recent reports it has been shown to have a high sensitivity and specificity for the identification of parathyroid adenomas.10,11 In addition, clinicians (endocrinologists and endocrine surgeons) are performing ultrasound as an office-based procedure and steadily gaining experience in the pre-operative detection of parathyroid adenomas.12 Despite the recent and improving success of ultrasound alone in identifying the location of parathyroid adenomas, re-operative cases often require further confirmation of location prior to exploration. Ultrasoundguided fine needle aspiration (FNA) of suspected parathyroid tissue has been described as a minimally invasive, highly specific localization test for both re-operative and initial parathyroid explorations.5,13-18 In this study we describe our experience using high resolution ultrasound combined with FNA as an office-based, surgeon-performed localization technique in selected patients with HPT and report the sensitivity and specificity of this procedure in 54 patients undergoing parathyroid exploration. METHODS Patients presenting for surgical evaluation of hyperparathyroidism were initially evaluated with a full history, physical examination, and review of the relevant laboratory studies. In patients who had had prior neck surgery, operative notes and pathology reports were reviewed whenever possible. The diagnosis of HPT was established by calcium and parathyroid hormone levels. Patients were considered to have HPT if their calcium and PTH levels were above normal, or if their calcium level was in the high normal range with a PTH above normal. In specific cases, additional testing was performed (24-hour urinary calcium measurement, bone density testing, vitamin D levels). All patients then underwent a diagnostic neck ultrasound as a routine part of their initial evaluation. The ultrasound was performed in the surgical clinic using the Aloka 4000 ultrasound machine and a small-parts 7.5 mHz probe (Aloka, Inc., Wallingford Conn.). Patients were positioned supine with their neck extended, and they underwent a full diagnostic ultrasound of the neck, with particular attention to areas suspicious for

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Fig 1. Longitudinal ultrasound view showing tip of needle (arrow) within a parathyroid adenoma. This biopsy was done in a 45 year-old female who had previously undergone unsuccessful parathyroid exploration. The PTH level in the aspirate measured 5400 pg/mL; she went on to have a focal exploration with removal of a left upper parathyroid adenoma and resolution of her HPT.

parathyroid tissue. If such an area was identified, an FNA under ultrasound guidance was performed in selected patients. Prior to evaluation, all but one patient also underwent a technetium-99 sestamibi scan, the results of which were reviewed during their initial clinic visit. All patients who had undergone prior neck explorations at our institution or elsewhere underwent a fiberoptic laryngoscopy with examination of vocal cord mobility prior to re-exploration. Fine needle aspirations were performed using a 22-gauge needle and 20- or 10-cc syringe attached to a biopsy needle holder. The needle was introduced into the center of the suspected parathyroid tissue under direct ultrasound guidance and negative pressure applied while the needle tip was gently moved back and forth within the lesion (Figure 1). Either one or two needle passes were performed; if the tip was clearly seen within the lesion on ultrasound on the initial pass, only one pass was made. Prior to removing the needle from the tissue, suction was released and the contents of the aspirate directly applied to a slide and immediately fixed in 95% ethanol for cytologic examination. The remaining contents of the syringe were diluted in 5 cc of normal saline, injected into a collection tube, immediately placed on ice, and sent for PTH analysis by immunoassay.

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Table I. Ultrasound characteristics typical for parathyroid adenoma24,25 Hypoechoic Homogeneous Well-defined Oblong, tear-drop, or oval shaped Polar artery on Doppler Located along the margins of the thyroid gland

Fig 2. Indication for biopsy in 54 patients undergoing parathyroid fine needle aspiration with ultrasound guidance.

All of the biopsies were well tolerated and there were no patient complications. A true positive FNA was defined as one where the PTH level was greater than 40 pg/mL in the aspirate and a hypercellular gland corresponding to the lesion seen on U/S was identified and removed at surgical exploration. If the aspirate was positive, this often obviated the need for further localization tests prior to surgical exploration. In re-operative cases with negative aspirates, further localization tests were obtained and exploration performed when at least two tests were concordant for location of the parathyroid adenoma. Patients who had had prior neck surgery underwent a focused exploration and those undergoing initial exploration underwent bilateral, 4-gland exploration. Intraoperative PTH assay was used to confirm successful excision of hyperfunctioning parathyroid tissue. All patients had serum calcium and PTH levels checked the morning following surgery. All statistical analysis was performed using Microsoft Excel software; mean values are expressed as mean ± standard deviation. RESULTS From 2000 -- present, 908 patients underwent parathyroidectomy at our institution. Of these, 54 (6%) patients underwent 57 ultrasound guided parathyroid biopsies. There were 3 patients who underwent FNA of 2 separate areas identified on ultrasound as suspected parathyroid lesions. The average age was 55 ± 13 years (range 25-77) and there were 39 females and 15 males. There were 49 patients with 10 HPT, and 5 with a history of renal failure resulting in tertiary HPT. Two of the 49 patients with 10 HPT had a known history of parathyroid carcinoma, and presented with suspected recurrence after prior exploration(s). There were 2 patients with recurrent laryngeal nerve injuries

from prior neck explorations as noted by both voice change and on preoperative laryngoscopy. Indications for FNA are listed in Figure 2. The most common indications were patients presenting with recurrent or persistent HPT following a prior parathyroid exploration (n = 29), or those presenting for their initial parathyroid exploration who had had prior thyroid surgery (n = 11). Additional indications included the sonographic identification of a mass with features characteristic of a parathyroid adenoma in an unusual location (carotid sheath, intrathyroidal), or a cystic mass in a location typical for parathyroid tissue. Ultrasound features characteristic of an enlarged parathyroid gland are listed in Table I, and ultrasound images of typical parathyroid adenomas are shown in Figure 3. Of the 57 biopsies performed, there were 44 aspirates in 43 patients where ultrasound identified a lesion characteristic for an enlarged parathyroid gland and the PTH level in the aspirate measured >40 pg/mL. At exploration, an enlarged gland was found in all 44 cases in the area indicated by the ultrasound; this was subsequently confirmed by pathologic analysis of the specimen as hypercelluar parathyroid tissue. There were therefore no false positive aspirates, for a specificity of 100%. The median PTH level in the positive aspirates was 11,665 pg/mL (range 44-13,000,000). Forty of the 44 positive aspirates had PTH levels of >500 pg/mL. There were only 4 positive aspirates with PTH levels <500 pg/mL; of these 4, 2 were aspirates from lesions that appeared cystic on ultrasound and at exploration were found to be parathyroid tissue with clearly cystic areas within the gland. The PTH levels in the 2 cystic glands measured 231 and 167 pg/mL. With regards to the cytology, 36 of the 44 positive aspirates had cytology consistent with benign parathyroid tissue. One patient with a history of parathyroid cancer had cytology from the aspirate consistent with recurrent parathyroid cancer; the PTH level in this aspirate measured 30,900 pg/mL. The cytology on the remaining 7 patients with positive PTH level aspirates included 4 nondiagnostic specimens and

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Table II. Summary of results from 57 ultrasoundguided FNA’s of suspected parathyroid lesions in patients presenting with HPT Enlarged, hypercellular gland found at biopsy site

PTH level in aspirate >40 pg/mL

Yes No

Yes

No

44 (true positive) 3 (false negative)

0 (false positive) 10 (true negative)

Sensitivity 94% Specificity 100% Positive predictive value 100% Negative predictive value 77% Overall accuracy 95%

Fig 3. Longitudinal views of a left upper (A) and left lower (B) parathyroid adenoma. The homogeneous, well-circumscribed, oblong-shaped appearance of these lesions located alongside the thyroid gland is classic for a parathyroid adenoma.

3 that were interpreted as thyroid follicular cells. Listed in Table II are the sestamibi results, the location of the biopsied gland identified on ultrasound, and the surgical findings in the 43 patients with positive aspirates. Six of 44 patients (14%) with true positive aspirates had sestamibi scans that were either negative (no parathyroid adenoma seen), or inaccurate. Of the 43 patients with positive aspirates, 33 were re-operative neck patients (21 had prior parathyroid surgery, 10 had prior thyroid surgery, and 2 had anterior cervical spine surgery). In all re-operative patients with positive biopsies, a focal exploration was performed guided by intraoperative PTH levels. Thirty-seven of the 43 re-operative

patients underwent a successful focal exploration with removal of a single parathyroid adenoma at the site indicated by the biopsy, one patient underwent focal exploration of 2 sites identified by U/S guided biopsy, and in the remaining 5 patients, further exploration was required. Thirty-four of the 43 patients with positive biopsies had normal calcium and PTH values on post-operative day #1, 4 patients with renal failure and one patient with parathyroid cancer had significant declines in their PTH levels, 3 patients had low/normal calcium levels with slightly elevated PTH levels, and one patient had persistent HPT with hypercalcemia and elevated PTH levels. In 10 aspirates performed in 9 patients, a lesion suspicious for parathyroid tissue was identified on ultrasound, a biopsy revealed a PTH level of <40 pg/mL, and at surgery in 8 patients an enlarged parathyroid gland was found in a different location; in one patient no parathyroid tissue was found. The median PTH level in these 10 aspirates was 8.5 pg/mL (range <4-15). Of these 10 true negative biopsies, 5 were identified on cytology as thyroid tissue, 3 as lymphoid tissue, and 2 as nondiagnostic. In 3 patients, a lesion suspicious for parathyroid tissue was identified on ultrasound, a biopsy revealed a PTH level of <40 pg/mL, and at surgery an enlarged parathyroid gland was found in the location of the preoperative biopsy. The aspirate PTH levels in these 3 false negative biopsies measured 23 pg/mL, <4 pg/mL, and <4 pg/mL and on cytology, they were identified as lymphoid tissue, thyroid tissue, and nondiagnostic respectively, which suggests that the needle missed the suspected parathyroid lesion.

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Table III. Sestamibi, ultrasound, and surgical findings in the 43 patients with 44 positive ultrasound guided fine needle aspirates (aspirate PTH level > 40 pg/mL)

Table IV. Weight in milligrams of the resected parathyroid glands FNA result

True positive (n = 44)

False negative (n = 3)

Patient Sestamibi scan Ultrasound

Mean weight Standard deviation Median Maximum Minimum

1754.9 1931.3 691.6 6240.0 33.3

215.8 65.4 249.6 257.4 140.4

1* 2 3 4 5* 6* 7 8 9 10 11* 12 13 14 15 16 17* 18 19 20 21 22 23 24 25 26# 27 28 29 30 31 32 33 34 35 36 37 38*

negative LU not done RL LU RL LL, RU LL, RL Left LU negative RL LL LL LL LL LU, LL, RL negative LL LU RL RL LSCM LU RL Left LL RU LU LU RL LU LU RL RU LU RSCM negative

39 40 41 42 43

RL RL LU LU RL

RL LU RU RL RL RU LL RU RL LU LL RL LL LL LL LU LU RU LL LU RL RL LSCM LU RL LL, LU LL RU LU LU RL LU LU RL RU LU RSCM Lymph node with parathyroid CA RL RL LU LU RL

Surgical findings RL, LU** LU RU RL RL RU LL, RU** All 4 glands** RL, LL** LU LL RL LL LL LL LU LU RU LL LU RL RL LSCM LU RL LL, LU LL RU LU LU RL LU LU RL RU LU RSCM Lymph node with parathyroid CA RL RL LU LU RL, LU**

*6/43 cases had sestamibi scan results that were either negative or inaccurate. **In 5 cases, additional glands were identified at exploration which were not identified on pre-operative ultrasound. #One patient had 2 areas that were aspirated as positive for parathyroid tissue; the patient was found to have hyperplastic parathyroid tissue in both locations identified by the biopsies.

Gland weight estimated with formula L 3 W 3 H/2.

With regards to the 3 patients who underwent biopsies of 2 separate areas, one patient had 2 positive aspirates and at exploration had 2 abnormal glands removed (patient #26 in Table 2). One patient had both a true positive and a true negative biopsy, and the third had 2 true negative biopsies, with a parathyroid adenoma identified in another area of the neck at exploration. The results of the biopsies are summarized in Table III and the mean gland weights of the true positives and false negatives are shown in Table IV. Of the 54 patients, who underwent exploration, forty patients had a single benign adenoma, 8 had double adenomas, 3 had 4-gland hyperplasia, and 2 had recurrent parathyroid carcinoma. One patient had a negative exploration. DISCUSSION An increasing number of endocrine surgeons are using ultrasound as an imaging modality in the office and operating room in the evaluation of patients with HPT.12 The performance of ultrasound by the surgeon may be particularly relevant in patients presenting for re-operative parathyroid surgery, where knowledge of the location of prior parathyroid resections from operative notes and pathology reports is essential in interpreting ultrasound findings. In addition, real-time examination of the ultrasound study is neccessary in order to distinguish hypoechoic structures such as the carotid artery, esophagus, and lymph nodes from enlarged parathyroid glands, this may be particularly essential in patients with ectopically located glands. Surgeons can correlate ultrasound findings with the results of additional studies such as sestamibi scan and MRI and accordingly plan their surgical approach. One of the most essential reasons for surgeons to perform their own ultrasound studies is the ability of the surgeon to then perform ultrasound-guided biopsies when indicated. Ultrasound-guided FNA as a localization procedure for parathyroid tissue was first described in 1981.13 In this report, a patient who had

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undergone several failed prior explorations had pre-operative localization of a parathyroid adenoma and subsequent successful surgery with resolution of his hyperparathyroidism. Following this case report, several studies have further investigated the use of this technique, confirming its efficacy and safety in the pre-operative localization of parathyroid adenomas. In 1994, Sacks et al published a report where 45 patients with 10 HPT underwent FNA of sonographically suspected parathyroid adenomas.14 Thirty-seven of the 45 patients had elevated aspirate PTH levels and all were confirmed at operation for a specificity of 100%. Twenty-five of these patients had had previous parathyroid explorations, the remainder had glands located inectopic or unusual locations. Also in 1994, MacFarlane et al described the National Institute of Health/National Cancer Institute experience with percutaneous FNA of suspected parathyroid neoplasms in patients undergoing re-operative parathyroid exploration.5 In this study, 42 patients underwent 44 FNA biopsies with either CT or ultrasound guidance, resulting in a sensitivity and specificity of 70% and 100%, respectively. The PTH level was used as the primary criteria for evaluation of the aspirate. There were 4 minor complications (3 small hematomas and 1 transient episode of bronchospasm), and the authors of the study concluded that image-guided FNA is a safe and highly specific procedure that, when resulting in a positive aspirate, obviates the need for further localization studies. Prior to these reports, Doppman et al reported the successful identification of parathyroid adenomas in 7/7 patients presenting with persistent or recurrent 10 HPT using CT guided FNA and PTH aspirate measurement prior to re-exploration.16 Gooding et al report similar excellent results in a study using either CT or ultrasound guided FNA and aspirate cytology to confirm the location of parathyroid tissue in 11 patients, all of whom underwent successful re-operation.15 Additional studies describe the use of ultrasound guided FNA for the localization of parathyroid adenomas in patients undergoing initial operation.17,18 Despite our belief that such a procedure is not indicated prior to an initial exploration, these reports confirm the safety and accuracy of parathyroid FNA. In our study, the PTH level was used as the primary determinant of a positive aspirate and cytology used as supporting data and to exclude alternate diagnoses. There is no established standard as to what level of PTH should be regarded as evidence that the aspirated tissue represents parathyroid tissue. As shown in our study, the PTH level in the aspirate is rarely equivocal; positive aspirates

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are frequently elevated into the hundreds or thousands of pg/mL and negative aspirates are typically <20 pg/ml or undetectable. As described in a prior publication on parathyroid FNA, the level of PTH in nonparathyroid tissue should theoretically be undetectable; blood contamination in biopsies of nonparathyroid lesions may explain the small amounts of PTH detected in negative aspirates.14 In addition, it is important to consider that the aspirate is rinsed and diluted and therefore the measured PTH level in the aspirate likely corresponds to a much higher concentration in the original sample.17 In general, the PTH level is considered to be more reliable than cytology in determining whether or not the sampled tissue is parathyroid, although a number of publications have described the use of cytology for the identification of parathyroid tissue.19,20 Also noted was a small but not insignificant number of false negative biopsies; this may occur if the lesion is of smaller size or in a more difficult location to access with a biopsy needle. In the true positive group, the mean weight of the glands removed was 1754.9 ± 1931.3 mg, whereas in the false negative group it was 215.8 ± 65.4 mg. Although the small number of patients in the false negative group precludes a meaningful statistical analysis, this suggests that smaller parathyroid adenomas may have a higher rate of false negative biopsies. Another study found that 4/5 patients with false negative parathyroid aspirates had enlarged or nodular thyroid glands and hypothesized that the coexistence of thyroid nodules may increase the likelihood of erroneous sampling.17 An obvious limitation of parathyroid FNA is that it is clearly not useful in patients with HPT who have a parathyroid adenoma located outside the cervical region or those in whom a cervical parathyroid is not detected on ultrasound. As technology improves and clinicians gain further experience with neck ultrasound, the detection rate of cervical lesions is sure to improve. CT scan has also been shown to be accurate in localization for parathyroid FNA.16 Ultrasound, however, is immediately available and able to be performed as an office based procedure. In addition, ultrasound allows for direct visualization of the needle within the lesion.18 CT scan may be more appropriate for the localization and biopsy of parathyroid adenomas located below the cervical region, an area not well examined with ultrasound. It is essential to consider that although a positive aspirate is a reliable result, a negative aspirate does not necessarily rule out the presence of parathyroid tissue in the sampled lesion. In those cases,

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noninvasive studies such as sestamibi, CT scan, and MRI are required to localize the lesion and in select cases, selective venous sampling and/or arteriography may also be useful. It is also important to keep in mind that parathyroid localization with ultrasound guided FNA does not exclude the possibility of abnormal parathyroid tissue elsewhere in the neck and intraoperative PTH is a useful adjunct when considering a focal approach. There were no complications in this current study, a similarly low complication rate is reported in other studies using parathyroid FNA for localization5,14 One concern is that the biopsy could cause a hematoma or adhesions around the gland and hence make the dissection more difficult. We did not notice scarring or hematoma of any significance in the parathyroid glands that were biopsied, nor did we note increased difficulty in removing the biopsied glands. It is noted in Sacks et al14 that minor adhesions were noted around biopsied parathyroid lesions and that although in no case did it result in surgical failure or complications, it did make the dissection more difficult. The possibility of minor adhesions must be factored in to the added information gained from a parathyroid biopsy in selected patients for whom preoperative localization is paramount. Another concern is that FNA of parathroid tissue could lead to parathyromatosis, the implantation of parathyroid cells in the tissues of the neck This could theoretically occur along the tract of the biopsy needle after violation of the capsule of the parathyroid gland. Overall, parathyromatosis is a rare occurrence, and has been primarily described in the context of recurrent hyperparathyroidism following a parathyroidectomy with rupture of the capsule during excision of the gland.21 Interestingly, parathyromatosis has also been described in patients with no prior neck surgery, or in areas of the neck remote in location from prior explorations, raising the proposed mechanism of diffuse parathyroid hyperplasia in embryological rests of parathyroid tissue.22 Kendrick et al investigated the risk of parathyromatosis in patients who had undergone parathyroid FNA for pre-operative localization and noted that of 81 patients with a mean follow-up of 5.8 years, none had developed parathyromatosis following parathyroid FNA.23 In this current study, we describe 54 patients who underwent 57 ultrasound directed biopsies for localization of enlarged parathyroid glands. Our goal was to describe the technique of ultrasound guided parathyroid biopsy, document its high specificity and positive predictive value, and confirm its safety. We conclude that ultrasound guided

parathyroid FNA performed in the surgeon’s office has the potential to streamline the number of costly and time-consuming appointments and reduce the number of expensive and often invasive studies prior to the surgical treatment of recurrent and persistent 10 HPT. In addition, parathyroid FNA of ectopically located or unusual appearing glands may prevent the need for re-operation in a small but significant number of patients for whom initial surgery is particularly challenging. REFERENCES 1. Lundgren E, Rastad J, Ridefelt P, Juhlin C, Akerstrom G, Ljunghall S. Long-term effects of parathyroid operation on serum calcium and parathyroid hormone values in sporadic primary hyperparathyroidism. Surgery 1992;112:1123-9. 2. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery 1994;116: 954-7. 3. Irvin GL 3rd, Sfakianakis G, Yeung L, Deriso GT, Fishman LM, Molinari AS, et al. Ambulatory parathyroidectomy for primary hyperparathyroidism. Arch Surg 1996;131:1074-8. 4. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002;235:665-70. 5. MacFarlane MP, Prater DL, Shawker TH, Norton JA, Doppman JL, Chang RA, et al. Use of preoperative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism. Surgery 1994;116:959-64. 6. Grant CS, van Heerden JA, Charboneau JW, James EM, Reading CC. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World J Surg 1986; 10:555-65. 7. Clark OH, Stark DD, Gooding GA, Moss AA, Arnaud SB, Newton TH, et al. Localization procedures in patients requiring reoperation for hyperparathyroidism. World J Surg 1984;8:509-21. 8. Chen CC, Skarulis MC, Fraker DL, Alexander R, Marx SJ, Spiegel AM. Technetium-99m-sestamibi imaging before reoperation for primary hyperparathyroidism. J Nucl Med 1995;36:2186-91. 9. Kern KA, Shawker TH, Doppman JL, Miller DL, Marx SJ, Spiegel AM, et al. The use of high-resolution ultrasound to locate parathyroid tumors during reoperations for primary hyperparathyroidism. World J Surg 1987;11:579-85. 10. Reeder SB, Desser TS, Weigel RJ, Jeffrey RB. Sonography in primary hyperparathyroidism: review with emphasis on scanning technique. J Ultrasound Med 2002;21:539-52. 11. Mazzeo S, Caramella D, Marcocci C, Lonzi S, Cambi L, Miccoli P, et al. Contrast-enhanced color Doppler ultrasonography in suspected parathyroid lesions. Acta Radiol 2000;41: 412-6. 12. Siperstein A, Berber E, Mackey R, Alghoul M, Wagner K, Milas M. Prospective evaluation of sestamibi scan, ultrasonography, and rapid PTH to predict the success of limited exploration for sporadic primary hyperparathyroidism. Surgery 2004;136:872-80. 13. Clark OH, Gooding GA, Ljung BM. Locating a parathyroid adenoma by ultrasonography and aspiration biopsy cytology. West J Med 1981;135:154-8. 14. Sacks BA, Pallotta JA, Cole A, Hurwitz J. Diagnosis of parathyroid adenomas: efficacy of measuring parathormone levels in needle aspirates of cervical masses. AJR Am J Roentgenol 1994;163:1223-6.

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15. Gooding GA, Clark OH, Stark DD, Moss AA, Montgomery CK. Parathyroid aspiration biopsy under ultrasound guidance in the postoperative hyperparathyroid patient. Radiology 1985;155:193-6. 16. Doppman JL, Krudy AG, Marx SJ, Saxe A, Schneider P, Norton JA, et al. Aspiration of enlarged parathyroid glands for parathyroid hormone assay. Radiology 1983;148:31-5. 17. Marcocci C, Mazzeo S, Bruno-Bossio G, Picone A, Vigaa UE, Ciampi M, et al. Preoperative localization of suspicious parathyroid adenomas by assay of parathyroid hormone in needle aspirates. Eur J Endocrinol 1998;139:72-7. 18. Tikkakoski T, Stenfors LE, Typpo T, Lohela P, Apaja-Sarkkinen M. Parathyroid adenomas: pre-operative localization with ultrasound combined with fine-needle biopsy. J Laryngol Otol 1993;107:543-5. 19. Chang TC, Tung CC, Hsiao YL, Chen MH. Immunoperoxidase staining in the differential diagnosis of parathyroid from thyroid origin in fine needle aspirates of suspected parathyroid lesions. ActaCytol 1998;42:619-24. 20. Bondeson L, Bondeson AG, Nissborg A, Thompson NW. Cytopathological variables in parathyroid lesions: a study based on 1,600 cases of hyperparathyroidism. Diagn Cytopathol 1997;16:476-82. 21. Sokol MS, Kavolius J, Schaaf M, D’Avis J. Recurrent hyperparathyroidism from benign neopkstic seeding: a review with recommendations for management. Surgery 1993; 113:456-61. 22. Kollmorgen CF, Aust MR, Ferreiro JA, McCarthy JT, van Heerden JA. Parathyromatosis: a rare yet important cause of persistent or recurrent hyperparathyroidism. Surgery 1994;116:111-5. 23. Kendrick ML, Charboneau JW, Curlee KJ, van Heerden JA, Farley DR. Risk of parathyromatosis after fine-needle aspiration. Am Surg 2001;67:290-3. 24. Frasoldati A, Valcavi R. Challenges in neck ultras o no graphy: lymphadenopathy and parathyroid glands. Endocr Pract 2004;10:261-8. 25. Karstrup S. Ultrasonically guided localization, tissue verification, and percutaneous treatment of parathyroid tumours. Dan Med Bull 1995;42:175-91.

DISCUSSION Dr Andrew Saxe (Flint, Michigan). In my experience, you get astronomical levels when you put a needle in a parathyroid. The ones with low values were these bloody samples such that you were collecting serum, and are you really reflecting serum levels rather than tissue levels? Dr Antonia Stephen (Cleveland, Ohio). Patients with borderline results often present a dilemma. If blood is biopsied from nonparathyroid tissue and the patient has a high serum PTH, it could potentially contaminate the result. We did not, however, note that the biopsies with lower PTH levels were bloody samples. As you mentioned, most of the aspirates were not equivocal, and an aspirate that is greater than 500 or greater than 1,000 reliably predicts the presence of parathyroid tissue at exploration. In patients with PTH levels elevated to a lesser degree, the individual case, as well as additional localization studies, should be taken into account to determine the reliability of a borderline biopsy result.

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Dr Carmen Solorzano (Miami, Florida). We have been performing ultrasonography ourselves as part of our physical examination in our clinic for about 4 years now, and we have extensive experience. Usually we don’t find a need to do an FNA, though I understand the need in some of the patients you showed. In how many of these patients did you find that the FNA changed how you were going to proceed? Because I think that you ended up probably going to the same spot that the ultrasound said in the majority of these patients. How many were intrathyroidal? Did you have thyroiditis present? You indicated you had 12 patients with an unusual location. Are you talking about the thyroid thymic ligament, which usually looks pretty clear on ultrasound scan—is that a parathyroid? Dr Antonia Stephen (Cleveland, Ohio). With regard to the first question, all patients who had a positive parathyroid biopsy result did not proceed to additional localization studies before exploration. This altered their management in that all reoperative patients normally require at least 2 concordant localization studies before surgery. We agree that the majority of patients with hyperparathyroidism do not require a parathyroid biopsy, and the presence of a classic-appearing parathyroid on ultrasound scan is a reliable finding. Could you please repeat your last question? Dr Carmen Solorzano (Miami, Florida). In what percentage did you have intrathyroidal parathyroids, thyroiditis, etc. that may have made you do the FNA? It is just that usually you don’t need the FNA, and even in the patient you presented, you were going to go anyway because probably the mibi didn’t show anything or you didn’t do a mibi, and that is the only spot that you see on ultrasound scan. Dr Antonia Stephen (Cleveland, Ohio). There were 6 intrathyroidal glands, which represented 11% of the glands biopsied. Although we did biopsy thyroid abnormalities such as nodules in many patients with hyperparathyroidism, we only included in this study those whom we suspected had intrathyroidal parathyroids. Dr Christopher R. Mchenry (Cleveland, Ohio). I wanted to make sure I understood you correctly. Based on the data that you have accumulated, when you have an ultrasound and the ultrasound-guided fine-needle aspiration biopsy is positive for PTH, am I correct in understanding you no longer do any further localizing tests? I think that would result in a significant change in clinical management. Dr Antonia Stephen (Cleveland, Ohio). All of our patients referred with hyperparathyroidism undergo a sestamibi scan before they present for their initial evaluation as part of an ongoing prospective trial. An ultrasound scan is then performed in the office, and in selected cases, an ultrasound-guided FNA is done. If it is positive, we proceed to exploration without further localization. If the biopsy result is negative in a reoperative patient, further localization studies are obtained. The parathyroid biopsy, therefore, helped avoid many expensive and often invasive localization studies.

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Dr Scott Wilhelm (Cleveland, Ohio). I would just comment, too, that for the intrathyroidal parathyroid adenoma, I think this technique has been very helpful. We have had 2 of these in the last 2 months. It really alters your operative management because you know you are going to be doing a thyroid lobectomy to start with, and it is nice to be able to counsel the patient ahead of time. My question to you is in 2 parts: One, on the levels at which you are getting iPTH values of 13 million, logistically when I send those off, I get a report back from the lab saying it is greater than 2,500 and is immeasurable. What are you doing in terms of your dilutions? Are you doing them yourself using the IO-PTH quick assay, or is your lab doing your dilutions? Second, on the 3 falsenegative values, did you take the operative specimens and aspirate them and send them to see what the values from the operative specimen looked like? I am sure it would be high, but I am just curious.

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Dr Antonia Stephen (Cleveland, Ohio). After aspirating the suspected lesion, we rinse the needle and syringe in 5 mL of normal saline, which is then sent for a routine PTH level, not an IO-PTH quick assay level. It is not diluted further in the lab. In terms of the false-negative glands, we did not aspirate the operative specimen for a PTH level. I think that is an excellent idea that could confirm the tissue as parathyroid, provide information regarding the range of PTH levels in aspirated glands, and supply material for further cytologic study of parathyroid glands. Dr Andrew Saxe (Flint, Michigan). I think there is also another setting perhaps in which it can be very helpful, and that is when there is a discrepancy between the previous operative note and your localization findings. So if the operative note states the right lower was removed and here is something on the ultrasound in the right lower, it is nice to have a tissue biopsy that confirms that that is truly a parathyroid.