Why We Reversed Our Position After 15000 Parathyroid Operations

ORIGINAL SCIENTIFIC ARTICLES

Abandoning Unilateral Parathyroidectomy: Why We Reversed Our Position after 15,000 Parathyroid Operations

James Norman, MD, FACS, FACE, Jose Lopez, MD, FACS, Douglas Politz, MD, FACS, FACE

BACKGROUND: Our group championed the techniques and benefits of unilateral parathyroidectomy. As our experience has matured, it seems this limited operation might be appropriate only occasionally. METHODS: A single surgical group’s experience with 15,000 parathyroidectomies examined the ongoing differences between unilateral and bilateral techniques for 10-year failure/recurrence, multigland removal, operative times, and length of stay. RESULTS: With limited experience, 100% of operations were bilateral, decreasing to 32% by the 500th operation (p Ͻ 0.001), and long-term failure rates increased to 6%. Failures were 11 times more likely for unilateral explorations (p Ͻ 0.001 vs bilateral), causing gradual increases in bilateral explorations to 97% at the 14,000th operation (p Ͻ 0.001). Ten-year cure rates are unchanged for bilateral operations, and unilateral operations show continued slow recurrence rates of 5% (p Ͻ 0.001). Removal of more than one gland occurred 16 times more frequently when 4 glands were analyzed (p Ͻ 0.001), increasing cure rates to the current 99.4% (p Ͻ 0.001). Of 1,060 reoperations performed for failure at another institution, intraoperative parathyroid hormone levels fell Ͼ50% in 22% of patients, yet a second adenoma was subsequently found. Operative times decreased with experience; bilateral operations taking only 5.9 minutes longer on average (22.3 vs 16.4 minutes; p Ͻ 0.001), which is 25 minutes less than unilateral at the 500th operation (p Ͻ 0.001). By the 1,000th operation, incision size (2.5 Ϯ 0.2 cm), anesthesia, and hospital stay (1.6 hours) were identical for unilateral and bilateral procedures. CONCLUSIONS: Regardless of surgical adjuncts (scanning, intraoperative parathyroid hormone), unilateral parathyroidectomy will carry a 1-year failure rate of 3% to 5% and a 10-year recurrence rate of 4% to 6%. Allowing rapid analysis of all 4 glands through the same 1-inch incision has caused us to all but abandon unilateral parathyroidectomy. (J Am Coll Surg 2012;214:260–269. © 2012 by the American College of Surgeons)

Primary hyperparathyroidism (pHPT) is a benign disease these small parathyroid tumors typically cause chronic fa- with malignant potential. Untreated, it is believed to carry tigue, memory loss, and a host of other nonspecific symp- a near 2-fold increase in development of several cancers (eg, toms associated with a considerable decrease in quality of breast, colon, prostate),1,2 and increases the risk of cardiac life.4,5 disease, hypertension, and stroke by more than double, Fortunately, pHPT is curable with removal of the source ultimately carrying a several-year decrease in life expec- of excess parathyroid hormone (PTH). In about 76% of tancy.3 Substantial if not severe osteoporosis will almost patients, the source is a single benign parathyroid tumor, always develop in affected patients, and 25% will get kid- and in the other 24% or so, there are 2, 3, or even 4 ney stones. Besides the damage to many organ systems, overproducing glands that need to be removed—all or in part.4 Because the number and location of the overproducing glands are variable and usually not known before oper- Disclosure Information: Nothing to disclose. Presented at the American College of Surgeons 97th Annual Clinical Con- ation, the surgical techniques for removing these parathy- gress, San Francisco, CA, October 2011. roid tumors have historically included evaluation of all 4 Received October 24, 2011; Revised December 12, 2011; Accepted Decem- parathyroid glands to determine which of the glands needs ber 14, 2011. to be removed. As such, parathyroidectomy has necessi- From the Norman Parathyroid Center, Tampa, FL. tated general endotracheal anesthesia and bilateral explora- Correspondence address: James Norman, MD, FACS, FACE, Norman Para- thyroid Center, 2400 Cypress Glen Dr, Wesley Chapel, FL 33544. email: tion; an operation that typically includes a generous neck [email protected] incision and several hours of operating time.

© 2012 by the American College of Surgeons ISSN 1072-7515/12/$36.00 Published by Elsevier Inc. 260 doi:10.1016/j.jamcollsurg.2011.12.007 Vol. 214, No. 3, March 2012 Norman et al Abandoning Unilateral Parathyroidectomy 261

be opened to remove another tumor. In retrospect, these Abbreviations and Acronyms tumors were present at the first operation, but were smaller IOPTH ϭ intraoperative parathyroid hormone and producing less PTH, so removal of the large parathy- pHPT ϭ primary hyperparathyroidism roid tumor gave the appearance that the patient was cured. PTH ϭ parathyroid hormone These patients did not have recurrent disease; they were never completely cured at their first operation. These patients had persistent disease, it just was not completely With the advent of the sestamibi scan in the early 1990s apparent for some months or years after the operation. came the concept that a surgeon could know with high It slowly become obvious within our practice that the certainty which patients harbored a single bad gland and its only way to achieve a near 100% long-term cure rate was to location. Armed with a localizing study, the operation evaluate the physiologic activity of all 4 parathyroid glands could be conducted with a unilateral approach, allowing in virtually all people at their first operation. As such, we for a quicker, smaller operation. Our group was a principal gradually gave up on unilateral parathyroidectomy in al- advocate for the unilateral approach, publishing numerous most every instance by the end of 2006. This study outlines articles between 1994 and 2005 touting the benefits of, the progression of this concept and the long-term results of and techniques used in, unilateral minimally invasive unilateral vs bilateral parathyroidectomy in 15,000 pa- parathyroidectomy.6-17 We published studies showing that tients. Lessons learned here have important implications the vast majority of patients were best served by a unilateral for all surgeons performing parathyroidectomy, regardless operation if they had a localizing study showing a single of their level of expertise. gland, provided that some form of physiologic measure of hormone production was performed in the operating room METHODS to help assure that the source of the excess PTH had been removed. This method of unilateral operation has now be- Study design come common throughout the world, with expected cure A retrospective analysis was conducted of prospectively col- rates in the low to mid-90% range, depending on surgeon lected data on 15,060 consecutive patients undergoing experience.18-21 parathyroidectomy by one surgical group during an 18- By 2005, volume of our practice had grown to Ͼ1,000 year period ending April 2011. All patients had primary parathyroid operations annually. With this volume came hyperparathyroidism; patients with secondary (renal) or the requirement of higher and higher cure rates, as a 3% to tertiary (post-transplantation) hyperparathyroidism are 6% long-term failure rate causes considerably greater not included. All patients were selected for surgery based follow-up and management problems with such high sur- on the biochemical diagnosis of pHPT as outlined in detail gical volumes. By 2010, our volume had exceeded 2,000 by our group recently.4 Preoperative scanning was never used parathyroidectomies per year, necessitating the very highest as a determinant of surgery vs no surgery. As outlined here, we cure rates available. A confounding issue for our practice do not perform any scan before the morning of surgery. was that many patients travel long distances to our center. Other patients not included in this study were those who A noncured patient who lives 3,000 miles away has differ- had undescended parathyroid tumors necessitating a ent implications for our practice than that noncured pa- nonstandard neck incision high in the neck and those with tient who lives within our community. Another confound- mediastinal tumors necessitating some form of thoracot- ing issue for our practice was the gradual but considerable omy, because evaluation of all 4 parathyroid glands is not increase in referrals of patients with negative scans who possible during these operations. All patients signed a con- were not being afforded surgery by surgeons in their com- sent for review of their clinical data, which was collected in munity because they could not localize an adenoma preop- a nonidentifiable fashion in accordance with principles eratively. As our surgical volume increased, so too did the outlined in the Declaration of Helsinki and as required for percentage of complex and/or scan-negative patients. our IRB approval. During the course of performing thousands of parathyroidectomies, it became clear that there was no maneuver Patient groups we could perform preoperatively or intraoperatively that For purposes of comparisons, the 15,060 patients have would assure us that all abnormal parathyroid tissue had been divided into 2 groups: group 1 consists of 14,000 been removed—short of the direct evaluation of the other patients undergoing their first parathyroid operation glands. Patients who we were convinced were cured some (which was performed by the authors). This group was years earlier were showing up again with abnormal calcium used to establish short and long-term cure rates for unilat- and/or PTH levels dictating that the other side of the neck eral vs bilateral operations within our practice. This group 262 Norman et al Abandoning Unilateral Parathyroidectomy J Am Coll Surg was also used to track operative times for unilateral vs bi- Performance of unilateral exploration lateral operations as the surgeons gained experience. Group Since our 500th operation, our approach to unilateral ex- 2 consists of 1,065 patients referred to our practice for plorations is exactly as it is for a bilateral approach, both are persistent pHPT.The subgroup being examined consists of performed through a 1-inch centrally placed transverse in- 233 patients who had 1 parathyroid adenoma removed at cision (incisions are never placed off to one side). When another institution (proven by pathology through size, performing a unilateral exploration, our policy is to iden- weight, and histology) using a unilateral operation; all had tify and examine the ipsilateral parathyroid gland; by pro- a Ն50% drop in serum PTH at 20 minutes (or later) after tocol, failure to identify an ipsilateral normal gland dictates removal of the parathyroid adenoma. that the operation be converted in almost all cases to a bilateral exploration. Removing a single adenoma and clos- Preoperative localization ing the wound is never done because we want to clear one Before referral to our center, 19% of the 14,000 first- side of the neck in case the patient is not cured, leaving the second operation to be performed on only the contralateral operation patients were sent to us with one (or more) pre- 16,18 operative scans that were read as positive; 65% had one or side, as described previously. If the second gland is en- more negative scans, and 16% were referred without any larged, nondormant, or in any other way abnormal, the localizing scans performed. All 15,060 patients in this operation is converted to a bilateral exploration. In our study underwent planar sestamibi scanning the morning of practice, and throughout the findings of this report, pa- the operation as the only localizing study. We do not scan tients who underwent a unilateral operation had a parathy- patients before the morning of the operation. Single- roid adenoma removed and the ipsilateral parathyroid photon emission computed tomography scanning was gland examined and determined to be normal. used occasionally for the first 1,000 or so patients and then abandoned in the mid-1990s. Ultrasonography is not used Performance of bilateral exploration by our group and was obtained on Ͻ12 patients. Similarly, Bilateral operations are conducted through the same inci- MRI was never used. CT scanning (4-dimensional and sion used for unilateral operations; the incision is not en- with single-photon emission computed tomographyϪ larged.4,16,18 Similarly, the type of anesthesia is unchanged. fusion as appropriate) is only used in our practice for pa- We have never use any form of deep venous thrombosis tients with tumors found to be in the deep mediastinum on prophylaxis nor have we used central lines, arterial lines, or planar sestamibi. CT scanning in its various forms is not bladder catheters. The positioning of the patient is supine used for routine preoperative localization and therefore in a slightly reverse Trendelenburg position with a roll none of the 15,060 patients in this study had CT scans placed transversely under the shoulders for neck extension. performed. Selective venous sampling has never been used in our practice for any patient. Anesthesia General endotracheal anesthesia was routinely used for the Determinant of unilateral vs bilateral exploration first 250 or so patients. Since that time, we have used la- A number of variables have been used by our group to ryngeal masked airway as our method of airway manage- determine good vs poor candidates for unilateral parathy- ment, combined with IV sedation using propofol and roidectomy. A recent publication of ours describes these midazolam as the primary agents. Approximately 2.6% of variables, identifying 18 specific objective parameters that patients are intubated, typically because of severe morbid 23 had a statistically significant impact on our decision to obesity, as reported by our group previously. We have undertake or avoid a unilateral operation.22 In summary, never used any form of nerve-monitoring endotracheal patients who had a unilateral exploration were required to tube. We made a few attempts at the use of local anesthesia have a clearly positive, in-focus sestamibi scan with solitary (field blocks) in the late 1990s and quickly abandoned this localization of radioactivity that is clearly distinct from the approach. We have not used any form of local anesthesia in thyroid (vague hot areas behind one thyroid lobe were not the past 13,000 patients. sufficient to warrant a unilateral approach). In addition, the remainder of the scan must be without any hint of Measurement of parathyroid gland abnormality, patients must be older than 25 years of age, hormone production have no family history of pHPT or MEN syndromes, no As previously reported by our group,24,25 we determine goiter or enlarged thyroid on either side of the neck, no history the physiologic activity of each parathyroid gland during the of lithium use, no history of neck radiation, and no history of operation as each gland is encountered, relying on the pituitary, adrenal, or pancreatic disease. gland’s metabolic activity rather than anatomic appearance Vol. 214, No. 3, March 2012 Norman et al Abandoning Unilateral Parathyroidectomy 263

or cellularity under a microscope to determine if it is abnormal. This 3-second computer analysis determines the amount of PTH being produced (quantitatively) by the measurement of contained gamma radioactivity (counts per second) compared against a standard curve of hormone production (reported as pg/mL), taking into consideration the volume of distribution of the patient and radioactive decay (half-life) since injection. In patients with pHPT, parathyroid glands can be quickly determined to be normal (dormant), a parathyroid adenoma, a hyperplastic parathyroid, or a clinically enlarged, nondormant parathyroid.24,25 Figure 1. Rate of unilateral parathyroidectomy and long-term cure By protocol, all glands that are nondormant are removed, rates for a single surgical practice performing 14,000 first-time 25 as described. Use of this technology allows us to eliminate operations. Unilateral parathyroidectomy (left vertical axis) was per- frozen-section analysis. The use of intraoperative PTH as- formed in 68% of patients early in our experience, decreasing sig- say (IOPTH) has never been used by our group. nificantly at every 1,000th operation, reaching a low of 3.3% at the 14,000th operation (p Ͻ 0.0001). The corresponding cure rate (right vertical axis) was at its lowest when the unilateral operative rate was Histology/pathology/photography highest, increasing at every 1,000th operation as the rate of bilat- Ͻ Routine use of frozen-section analysis was discontinued eral operations increased (p 0.0001). after approximately 750 patients, and by 2,000 patients it had been used on Ͻ1% of all parathyroid operations (typ- RESULTS ically reserved for occasional intrathyroid parathyroid tu- Disease profiles mors).25,26 Permanent histology, however, is obtained on all The average age in this study was 59.9 Ϯ 12.9 years (range specimens. Similarly, for the last 8,000 patients, all re- 9 to 105 years). Women constituted 75.1% and 24.9% moved parathyroid tumors were documented by photog- were men. The 3-year mean preoperative serum calcium Ϯ raphy. Weights of removed parathyroid tissues (of all types) level was 10.9 0.6 mg/dL and the 3-year preoperative PTH was 105.8 Ϯ 48 pg/mL. Mean highest calcium level have been recorded for all removed parathyroid glands Ϯ from all 15,000ϩ patients in this study. of each patient was 11.4 0.5 mg/dL and mean highest PTH was 115 Ϯ 52 pg/mL. A very detailed look at the biochemical profiles from 10,000 of these patients can be Operative times and length of hospital stay found in a recent publication from our group.4 Operative times are recorded in the electronic medical record system by the operating room nurse. Similarly, length Rates of unilateral vs bilateral operations over time of stay in the recovery room before discharge to home is Figure 1 shows the rate of bilateral vs unilateral operations recorded by the nursing staff in the medical record. Virtu- during 18 years and 14,000 patients who underwent their ally all patients in this study were discharged to home di- first operation with the authors (solid line, left-hand verti- rectly from the recovery room. The postoperative length of cal axis). Bilateral operations were the rule early in our stay is determined by the nursing staff, which is at all times experience, which quickly turned to be predominately uni- th unaware which patients had unilateral operations and lateral by the 600 patient (p Ͻ 0.0001). At that time, the those that had bilateral operations. percentage of unilateral explorations was at its highest at 68%. During the next 15 years, the percent of unilateral operations decreased at every 500th patient (p Ͻ 0.05). By Follow-up and analysis the 5,500th patient, our indications for unilateral explora- Follow-up is 100% at 6 months, 99.5% at 1 year, 99% at 2 tion were becoming more select; only 20% of operations years, and 97.7% at 5 years and consists of serial calcium, were unilateral (p Ͻ 0.001 vs 4,000). This trend contin- ionized calcium, and PTH. Minimum follow-up is 6 ued, by our 10,000th patient, Ͻ10% had a unilateral op- months. Mean follow-up is 5.9 Ϯ 3.3 years (range 6 eration. Currently, 3.3% of all patients referred to our prac- months to 18 years). Data are expressed as mean Ϯ SD and tice undergo a unilateral parathyroidectomy (p Ͻ 0.0001 analyzed using SPSS 11.0 (SPSS Inc). Differences between vs 1,000 through 10,000). Importantly, during this time groups were assessed by independent t-test, chi-square the rate of positive sestamibi scans increased from 74.8% to analysis, and ANOVA as appropriate; p Ͻ 0.05 was con- 80.1% (p ϭ 0.02; all scans interpreted by a single author, sidered significant. JN). During the time when our percentage of positive ses- 264 Norman et al Abandoning Unilateral Parathyroidectomy J Am Coll Surg

Figure 2. Ten-year cure rates after unilateral vs bilateral parathyroidectomy. The cure rates of 14,000 patients undergoing unilateral Figure 3. Mean operative time for bilateral vs unilateral parathyroid- vs bilateral exploration demonstrate signiﬁcant differences (p Ͻ ectomy for a single surgeon during 14,000 operations. Operative 0.001) at all time points. Long-term cure rates for patients under- times for both surgical approaches decreased as experience was going a bilateral operation do not change over time (p ϭ 0.93), and gained (p Ͻ 0.0001). Similarly, the difference in the time required to recurrent disease develops by 10 years post surgery in at least 5% perform a bilateral vs unilateral operation decreased at every of those believed to be cured after undergoing a unilateral operation 1000th operation (p Ͻ 0.01). (p Ͻ 0.001 at 2 years and beyond). their cure rates are significantly less at the time of surgery tamibi scans increased, our rate of unilateral exploration (p Ͻ 0.001 compared with bilateral), and their cure rates decreased. continue to drop for at least the subsequent 10 years (p Ͻ 0.0001 unilateral at time 1 year vs unilateral at 2 years and Cure rates over time beyond). Also shown on Figure 1 (dashed line, right-hand vertical axis) is the cure rate over time for all 14,000 patients un- Operative times for bilateral vs dergoing their first operation at our center (mean duration unilateral operations of follow-up is 5.9 Ϯ 3.3 years; minimum follow-up of 6 Operative times for the authors to complete bilateral and months; range 6 months to 18 years). As the percentage of unilateral parathyroid operations are shown in Figure 3 as a unilateral operations decreases, the long-term cure rate in- function of surgeon experience. As surgeon experience increases (p Ͻ 0.001). Despite developing a very conservative creases, operative times decrease (p Ͻ 0.001), with most of approach to unilateral operations, we could not achieve the decreases seen in the first 5,000 patients, but continu- Ͼ98% cure rate until our indications for unilateral opera- ing beyond 14,000 patients. Unilateral parathyroidectomy tions were so strict that Ͻ13% of our operations were also becomes faster with surgeon experience (p Ͻ 0.001). unilateral. The difference in time required to perform a bilateral vs unilateral operation decreases significantly (p Ͻ 0.05) at Cure rates over time for bilateral vs every 500th patient. By the 14,000th patient, a unilateral unilateral operations parathyroidectomy took the authors a mean of 16.4 Ϯ 3.3 The cure rates for 14,000 patients undergoing their first minutes (range 7 to 39 minutes, mode 14 minutes). Simi- operation at our center were divided into those undergoing larly, a bilateral parathyroid operation took a mean of Ϯ a bilateral vs unilateral parathyroid operations. Figure 2 22.3 7.4 minutes (range 12 to 91 minutes, mode 18 th shows the cure rates over 10 years, demonstrating that the minutes). By the 13,000 operation, the mean time differ- Ϯ vast majority of failures in our practice come from the ence between a unilateral and bilateral operation is 5.9 group of patients who underwent a unilateral operation 3.7 minutes. (p Ͻ 0.001 vs bilateral at all time points). Although not all patients undergoing a bilateral operation are cured, those Postoperative stay for bilateral vs that are believed to be cured at the time of operation con- unilateral operations tinue to be cured long term (p ϭ 0.93 for 1-year vs 10-year Only 212 of the 15,060 patients in this study were kept in cure rates for patients undergoing bilateral exploration). the hospital overnight (1.4%); 143 of them had a concom- Once cured after undergoing a bilateral operation with itant thyroidectomy and the need for overnight stay was examination of all 4 glands, a second de novo parathyroid not related to the extent of the parathyroid operation, as tumor almost never develops, even when patients are fol- reported previously.27 Of the most recent 13,000 patients, lowed for 15 years (p ϭ 0.88 year 1 vs 15 years). The same 99.6% were discharged from the recovery room. Mean du- is not true for patients undergoing unilateral exploration; ration of hospital stay (from admission into the recovery Vol. 214, No. 3, March 2012 Norman et al Abandoning Unilateral Parathyroidectomy 265

Table 1. Number of Parathyroid Glands Removed in Unilateral vs Bilateral Operations Unilateral exploration Bilateral exploration p Value (3,000 ؍ n) (3,000 ؍ Variable (n Single gland removed, % 96.9 75.3 Ͻ0.0001 Two glands removed, % 3.1 16.7 Ͻ0.0001 Three glands removed, % 0 5.1 Ͻ0.001 3.5 glands removed, % 0 2.9 0.03 The number of parathyroid glands removed during 3,000 unilateral operations was dramatically lower than the number of glands removed during 3,000 bilateral operations.

room to discharge from the hospital, which is at the discre- rates equal to that seen with a bilateral approach (p Ͻ tion of the recovery room nurses) was 98 Ϯ 14 minutes for 0.001). unilateral explorations and 100 Ϯ 15 minutes for bilateral operations (p ϭ 0.87). Number of glands removed The number of parathyroid glands removed during the Causes of failures in 14,000 ﬁrst-time most recent 3,000 bilateral operations is compared with the parathyroid operations most recent 3,000 unilateral operations in Table 1 (to elim- At the 500th patient, the failure rate (noncure, as defined inate surgeon experience as a variable). The number of here previously) for bilateral explorations was 2.8%. At the abnormal glands removed when performing a bilateral op- 14,000th patient, the noncure rate for bilateral explorations eration is dramatically higher than during a unilateral op- was 0.7% (p Ͻ 0.001). The cause of the failure in bilateral eration, even for experienced surgeons using very conser- operations was the lack of finding any abnormal gland in vative criteria for which patients are selected for unilateral 31% of noncured patients (known to be noncures at the exploration. When all 4 parathyroid glands are examined time of surgery), and the failure to find a second (or third) and their physiologic activity determined, we remove more abnormal gland in 69% (known to be noncures only after than one gland in 24.7% of patients. In patients with a some days or weeks after the operation was concluded). clearly positive sestamibi scan (meeting our criteria for a Within the unilateral group, the cause of the noncure unilateral exploration) who undergo bilateral exploration, was exclusively due to the failure to recognize multigland we remove more than one gland in 19.6% of patients. disease. Because our protocol has always been to (attempt to) examine the ipsilateral gland during a unilateral explo- Second adenomas removed after a 50% or more ration, 97.8% of failures were due to missed second (or drop in intraoperative PTH more uncommonly, third) adenoma on the contralateral Table 2 shows the percent drop in PTH measured during side. At the 1,000th patient, the 5-year cure rate for unilat- 233 unilateral operations performed at another institution, eral operations was 93.8%. At the 10,000th patient, using a which were subsequently referred to our center for reopera- much more conservative selection criteria for unilateral ex- tive surgery because of noncure. All patients in this group ploration, the cure rate for a unilateral exploration was had a Ͼ50% drop in PTH at 20 minutes (or more) postex- 97.2% (p Ͻ 0.001 vs 1,000th patient). Regardless of how cision of an adenoma (required to be in this study group) conservative our application of the unilateral technique with all but 9 (96%) having the IOPTH level fall into the even after 10,000 operations, we could not achieve cure normal range. Before their first operation, these 233 pa-

Table 2. Findings at Second Parathyroid Operation after Ͼ50% Drop in Parathyroid Hormone during First Operation Findings at second operation Patients 1 additional 2 additional Drop in PTH, % n% adenoma adenomas p Value 50Ϫ59 49 21 39 10 0.006 60Ϫ69 81 35 75 6 Ͻ0.001 70Ϫ79 61 26 58 3 Ͻ0.001 80Ϫ89 30 13 28 2 0.005 Ͼ90 12 5 12 0 0.11 A total of 233 patients were referred for a second operation following the removal of one parathyroid adenoma and a greater than 50% drop in PTH levels at 20 minutes post adenoma resection. PTH, parathyroid hormone. 266 Norman et al Abandoning Unilateral Parathyroidectomy J Am Coll Surg

tients had mean highest serum calcium and PTH levels of forming Ͼ17,000 parathyroid operations; the only way to 11.3 Ϯ 0.4 mg/dL, and PTH of 121 Ϯ 28 pg/mL, respec- achieve 10-year cure rates Ͼ94.5% (even by the most ex- tively. By 1-year postoperation, the mean serum calcium perienced parathyroid surgeons), is to examine all 4 para- and PTH levels were 11.0 Ϯ 0.3 mg/dL and 94 Ϯ 29 thyroid glands in nearly all patients, avoiding the allure and pg/mL. Mean time between first operation and referral to attraction of the unilateral approach. The recent literature our center for a second operation was 2.1 Ϯ 0.8 years is full of reports from numerous groups touting high cure (range 2 weeks to 8.5 years). Table 2 also shows the findings rates with unilateral operations using IOPTH assays. Un- at the second operation where the other 3 parathyroid fortunately, these patients are highly selected in nearly ev- glands were evaluated. The drop in PTH values Ͼ50% ery case, with patients having a negative scan (or scans) not during the first operation did not prove that there were no operated on and therefore not included in the analysis. The other glands, nor was it predictive in any way of how many reader is encouraged to examine the operative selection other abnormal glands were present. Even patients with criteria in all these reports, as nearly 20% of our referrals IOPTH levels falling Ͼ90% had missed second adenomas. result from other surgeons refusing to operate without a As seen in Table 2, the higher the percentage of PTH drop positive scan. after removal of an adenoma, the higher the chance that The ultimate test for any approach to parathyroidec- only one additional bad gland would be present if the pa- tomy is long-term cure of the disease. Our group uses the tient was not cured. After their second operation, all 233 strictest definition of cure, ie, serum calcium level must patients were cured (as defined here) with the mean cal- remain Յ10.0 mg/dL and the serum PTH must remain cium and PTH levels 1-year postoperatively being 9.6 Ϯ Ͻ65 pg/mL. Although some authors would argue that 0.1 mg/dL and 32 Ϯ 7 pg/mL, respectively. cured patients can often have elevated PTH levels for some time after surgery,33,34 we rarely see this phenomenon largely because of our aggressive calcium supplementation DISCUSSION postoperatively.35,36 Therefore, any patients with persistent Although our group was a dominant driving force for uni- elevations of PTH postoperatively (Ͼ75 pg/mL) are con- lateral parathyroidectomy through the 1990s and early sidered noncured by our group until proven otherwise. 2000s, we have all but abandoned this approach. As we These uncommon patients are followed closely for years have tweaked and manipulated the indications and tech- until the final disposition is known. Similarly, after evalu- niques used in parathyroid surgery for many thousands of ating tens of thousands of patients with pHPT, we have patients, we have concluded that the promises of unilateral learned that adults older than age 30 years with normal explorations do not live up to the hype for the long term. parathyroid function should have calcium levels in the 9s, This is especially true when all patients with pHPT are not in the 10s (regardless of the upper limit of normal, given the opportunity to have a curative operation, even if which includes children and teens).4 That is, frequent or their localizing scans are negative. We believe there is a role persistent calcium levels (in an adult) Ͼ10.0 mg/dL indi- for unilateral exploration, however, its role at high-volume cate that a parathyroid tumor is present in nearly all cases. centers or centers of excellence should be minimized. Seeing calcium levels in the 10s in any postoperative pa- The underlying precept of a unilateral parathyroid op- tient indicates to us that the patient is not cured (unless the eration is the conviction that some form of preoperative or corresponding PTH is Ͻ15 pg/mL) and additional over- intraoperative testing can be trusted to rule out any addi- producing parathyroid tissue is presumed to be present. tional abnormal, overproductive parathyroid gland(s). Our Figure 1 illustrates the progress of our thoughts about experience documented in this report shows that no matter parathyroid surgery and our quest of many thousands of what the imaging techniques (and the expertise of the team patients to find a way to perform a unilateral operation that performing the scans), the status of all 4 glands cannot be would yield a long-term cure rate of Ն99%. To avoid fail- known preoperatively. Additionally, we also provide evi- ures, we are developing protocols that dictate when an at- dence that there is no intraoperative measure or test that tempted unilateral operation be converted to bilateral.22 can be performed, short of examining all 4 parathyroid Even with this 11% conversion rate of good candidates for glands, which can assure no other abnormal, overproduc- unilateral operation to a bilateral operation, we could not ing parathyroid gland is present. Our experience, along get our 6-month cure rates Ͼ96.5% or our 3-year cure with the first-hand experience of many others,28-32 has rates Ͼ95%. Our analysis showed that virtually all non- shown that IOPTH assays cannot be used to definitively cures came from patients who had a unilateral operation. determine the status of other parathyroid glands and there- As illustrated in Figure 1, as our experience grew we con- fore, cannot assure cure. It has become apparent after per- tinuously decreased the indications for unilateral explora- Vol. 214, No. 3, March 2012 Norman et al Abandoning Unilateral Parathyroidectomy 267

tion, and our rate of bilateral exploration increased. By the simply no mechanism to assess the functional status of 11,000th operation, we had decreased the indications for these other glands without physically doing so. Although unilateral exploration so dramatically that we essentially there might be some controversy about our nomenclature gave up on this approach altogether. It is important to of these additional abnormal glands that are removed (be- remember that we use no qualifying test to determine who cause we do not use histology and all historical reports of is operated on and who is not. That is, this report includes abnormal parathyroid glands use histology and gland cel- all types of pHPT from normocalcemic pHPT to severe lularity as the backbone of their nomenclature system), hypercalcemic pHPT, all of whom are operated on without there is no doubt that these glands are enlarged and over- the requirement for any type of positive localizing study. producing hormone. In fact, our removal of more than one The only patients we consider for a unilateral approach parathyroid gland in nearly 25% of cases is in line (or would be those with special circumstances, such as follow- slightly higher) than that seen with other experienced ing a previous neck dissection for cancer, or a patient who groups when all 4 glands are assessed.28,29 Importantly, the has undergone a previous thyroidectomy. literature is now full of reports of patients cured after their Figure 2 shows a dramatic decrease in total operative unilateral parathyroid operation, yet the follow-up in times, factored heavily into our decisions to eliminate uni- nearly all of these reports is Ͻ1 year. This study demon- lateral operations. Through thousands of operations we strates that 1-year cure rates are meaningless in patients learned a number of techniques that allowed us to perform undergoing unilateral parathyroidectomy. bilateral operations faster than we could perform unilateral Unilateral parathyroidectomy with the removal of one operations some years earlier. As the time differential be- parathyroid tumor followed by IOPTH assay to determine tween a unilateral and bilateral operation decreased to a a 50% drop in PTH as an indicator of cure has become matter of 6 minutes or so, the rewards of performing a popular during the past decade because it allows surgeons unilateral exploration became less attractive. Clearly, the of various experience levels to perform a successful opera- most important aspect of rapid parathyroid surgery has tion on a patient with a positive scan. However widespread become the use of the gamma probe as the single determi- this method is, it remains controversial and discounted by nant of parathyroid gland activity and, therefore, the ulti- some experts because of its associated false-positive and mate decision maker of whether a parathyroid gland is false-negative rates.29 Removal of one parathyroid tumor abnormal and removed or normal and left in place. This (typically without proving the ipsilateral gland is normal) 3-second analysis completely eliminates frozen-section flies in the face of what is known about the number of analysis and the time that it requires, and eliminates the abnormal glands removed when all 4 glands are assessed. vague, unhelpful information it typically provides.37 The Most surgical reports throughout the history of this disease actual surgical techniques we have learned are the subject of show that somewhere between 20% and 25% of patients an upcoming series of technical articles but, as stated in have more than one parathyroid gland removed when all 4 numerous publications, we do not put the gamma probe glands are examined, which is in line with the nearly 25% into the wound as is commonly thought—we do not use of patients who have more than one gland removed in the the probe to find parathyroid tumors. The probe is not a current report (with bilateral exploration). Other studies tumor-detecting tool, but rather it is an ex vivo hormone- have used IOPTH assays after adenoma removal and before measuring device.24,25 evaluation of all 4 glands and have shown that the IOPTH Probably the single most important finding of this study assay underestimates the presence of additional parathy- is that patients believed to be cured after a unilateral explo- roid tumors in 16% of cases.29 Although the current study ration can turn out to be only “better” and not cured, as does not take into account all of the unilateral parathyroid cure rates after unilateral exploration continue to decrease operations performed by surgeons who were associated for at least 10 years. Long-term cure rates are affected pri- with failures sent to our center—and the overall cure rate is marily by the following 2 variables: experience of the sur- not known—it does include the largest cohort of uncured geon and extent of the operation. In this study, one surgeon parathyroid patients who had a Ͼ50% drop in PTH dur- (JN) participated directly in Ͼ98% of the operations, so ing their operation. Using IOPTH during the operation surgeon expertise is eliminated as a variable except as the appears to simply tell the surgeon that they removed a experience increases with time. The difference in long-term parathyroid tumor that is overproducing PTH—a fact that cure rates between unilateral and bilateral explorations is the surgeon usually already knew. That is, a drop in shown in Table 1 and is due to the number of abnormal IOPTH of Ͼ50% and into the normal range tells the sur- parathyroid glands removed when all 4 parathyroid glands geon that the removed gland is a parathyroid adenoma that are evaluated. We have come to the conclusion that there is is making a large amount of PTH. It does not necessarily 268 Norman et al Abandoning Unilateral Parathyroidectomy J Am Coll Surg provide comment on the status of the other 3 glands. It Author Contributions seems clear that a drop in serum PTH by 50% (or even Study conception and design: Norman, Politz 90%) simply cannot definitively determine that all of the Acquisition of data: Norman, Lopez, Politz other glands are dormant (normal). Analysis and interpretation of data: Norman, Lopez, Politz Unilateral parathyroidectomy has 2 major benefits that Drafting of manuscript: Norman, Politz cannot be denied. First, any patient who is not cured after Critical revision: Norman, Lopez, Politz such an approach is able to undergo a simple, noncomplex second operation that is performed in virgin tissues. Sec- ondly, the unilateral approach allows many surgeons with a REFERENCES lack of specific training in parathyroid surgery to take care 1. Almquist M, Manjer J, Bondeson L, Bondeson AG. 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