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Factors associated with late recurrence after parathyroidectomy for primary hyperparathyroidism
Surgery xxx (2019) 1e6
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Factors associated with late recurrence after parathyroidectomy for primary hyperparathyroidism Reema Mallick, MD, Kristina J. Nicholson, MD, Linwah Yip, MD, Sally E. Carty, MD, Kelly L. McCoy, MD* Division of Endocrine Surgery, Department of Surgery, University of Pittsburgh Medical Center, PA
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a b s t r a c t
Article history: Accepted 1 May 2019 Available online xxx
Background: A recent study with unusually lengthy follow-up after surgery for primary hyperparathyroidism reported higher recurrence rates than previously appreciated. We sought to identify specific factors associated with late recurrence after seemingly curative parathyroidectomy. Methods: Prospectively collected data were retrieved for patients who had surgical treatment of sporadic primary hyperparathyroidism with 3-year follow-up (3e17.6 years). Recurrence was defined by 6 months of eucalcemia with subsequent hypercalcemia and a high or unsuppressed parathyroid hormone. Recurrent patients were compared with cured patients (defined by consistent eucalcemia). Results: Among 261 patients, 28 (10.7%) had recurrence and 233 (89.3%) were cured. The mean time to recurrence was 77 months (range 13e170). The mean final intraoperative parathyroid hormone (49.0 pg/mL vs 37.5 pg/mL, P < .01), 6-month calcium levels (9.6 mg/dL vs 9.2 mg/dL, P ¼ .02) and mean 6-month parathyroid hormone levels (86.5 pg/mL vs 59.6 pg/mL, P ¼ .04) were higher for recurrence. By multivariable analysis, 6-month calcium 9.7 and eucalcemic elevation of the parathyroid hormone at 6 months were independently associated with recurrent primary hyperparathyroidism. Conclusion: Long-term follow-up after apparent curative surgery for primary hyperparathyroidism identified a high late recurrence rate (10.7%), up to 17 years later. A 6-month calcium >9.7 mg/dL and eucalcemic parathyroid hormone elevation at 6 months may be associated with recurrence, and such findings may help guide management. © 2019 Published by Elsevier Inc.
Introduction Primary hyperparathyroidism (PHP) is an increasingly common endocrinopathy with a minimum of 100,000 new cases in the United States annually.1 Most patients are detected incidentally on routine biochemical testing.2 Failure to treat affected patients leads to increased risk for renal, bone, and cardiovascular disease, and decreased quality of life, which ultimately results in greater healthcare costs.3,4 Surgical extirpation is the only curative treatment for PHP, and cure rates have been routinely described in excess of 95% in the hands of experienced, high-volume surgeons.3,5,6
Presented at the 2019 Annual Meeting of the American Association of Endocrine Surgeons. * Reprint requests: Kelly L. McCoy, MD, Division of Endocrine Surgery, 3471 Fifth Ave, Suite 100, Kaufmann Building, Pittsburgh, PA, 15213. E-mail address: [email protected] (K.L. McCoy). https://doi.org/10.1016/j.surg.2019.05.076 0039-6060/© 2019 Published by Elsevier Inc.
For decades, cure in hyperparathyroidism has been defined as restoration of eucalcemia for a minimum of 6 months postoperatively.3,7 However, the durability of surgical cure long term was recently challenged by a report that longer length of followup may yield higher rates of late failure. In a single-institution study of 196 patients who were biochemically cured at > 6 months with subsequent follow-up for 5.4 to 10.9 years (median 9.2 y), there was a 14.8% relapse rate,8 in stark contrast to historical data sets.3,9e12 Recurrent PHP is a challenging problem for both patients and providers because those effected continue to be at risk for the symptoms and associated morbidities of PHP. Moreover, attempts at cure in the reoperative setting have higher costs and risks, including operative failure.3,13,14 In a large, long-term single-institution study, we aimed to determine the rate and pattern of onset for recurrence and to identify novel associated factors that may affect management, particularly in early postoperative surveillance.
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Methods Study design Using an institutionally approved (QI#1651) parathyroid database, prospectively collected clinical data were retrieved for all patients who underwent initial surgery for sporadic PHP from November 1995 to January 2015 with long-term follow-up, defined as >36 months of postoperative biochemical evaluation. Patients were then excluded if they underwent concomitant thyroidectomy, had parathyroid exploration without use of intraoperative parathyroid hormone (IOPTH) monitoring, had hypercalcemia within 6 months of surgery (persistent PHP), or had parathyroid cancer. Cure was defined by eucalcemia at 6 months after surgery. Long-term cure of primary hyperparathyroidism (CP) was defined by consistent eucalcemia for at least 3 years, through the most recent date of follow-up. Recurrent disease (RP) was defined by postoperative eucalcemia at 6 months, with subsequent hypercalcemia plus high or inappropriately unsuppressed parathyroid hormone (PTH) levels. To compare the CP and RP groups, demographic and perioperative data, including operative conduct; number of glands resected; gland weight; and IOPTH results, including percentage decline from baseline value, were extracted from the database. All charts for patients with suspected RP were carefully reviewed to confirm biochemical recurrence and the specific timing of calcium and PTH elevation, including calcium, 25-OH Vitamin D, and intact PTH at 6 months and afterward; total duration of follow-up; and time to recurrence, if applicable. All available calcium and PTH levels were reviewed for the duration of follow-up. Preoperative evaluation and surgical management
who appeared at any time to have RP routinely received detailed evaluation either by endocrinology or endocrine surgery to exclude confounding diagnoses and conduct surveillance long term. Statistical analysis Statistical analysis included use of Student’s t test for evaluation of continuous data and the Fisher exact test for categorical data. Association with PHP recurrence was assessed using logistic regression (Stata SE, v 14.0, StataCorp, College Station, TX, USA). A P value <.05 was considered significant. Results Patient characteristics Of patients who had surgery for PHP during the study period, 261 met inclusion criteria (Fig 1), 82% were women, and the mean age was 60.2 years (range 24e88). A total of 28 patients (10.7%) had RP and 233 (89.3%) had CP. Gender (RP 85.7% women versus CP 81.5%, P ¼ .8) and mean age (RP 59.6 years versus CP 60.2 years, P ¼ .6) were similar between groups. The mean highest preoperative calcium level was similar for RP (11.57 mg/dL, SD 0.520) and CP (11.47 mg/dL, SD 0.992) patients (P ¼ .6), and the mean highest preoperative PTH level was not significantly different (RP 194.4 pg/ mL, SD 182.8 versus CP 161.1 pg/mL, SD 130.8; P ¼ .4). Preoperatively, 94% of patients had both calcium and PTH levels concurrently above the upper limit of normal, as presented in Table I. High normal calcium levels were present in 10 patients (10 mg/dL to <10.2 mg/dL) along with PTH levels > 65 pg/mL, and these cases (3.8%) can be classified as normocalcemic PHP. In addition, 5 patients had inappropriately unsuppressed PTH levels from 54 to 63.8 (high normal 65 pg/mL) with concurrently elevated calcium levels (10.9 mg/dLe11.6 mg/dL). In this study there were no observed cases of permanent hypoparathyroidism or permanent recurrent laryngeal nerve dysfunction complicating surgery.
For all patients, the diagnosis of PHP was reached biochemically.3 Before operative intervention, imaging studies were performed using the optimal modality available at the time. In brief, we used 99mTc-sestamibi until 1997, used Sestamibi-SPECT from 1997 to 2010, added routine ultrasound in 2005, and used SPECT-CT plus ultrasound from 2010 to the present. Based on preoperative evaluation and guided by intraoperative findings and IOPTH results, patients underwent unilateral or bilateral exploration under general or cervical block anesthesia, and beginning in 2004 for selected patients, a video-assisted minimally invasive approach was used.15,16 Resected parathyroid tissue was routinely weighed, and tissue identity was typically confirmed by either frozen section analysis or intraoperative PTH tissue aspirate. Routine IOPTH monitoring was implemented in 1995 (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA until 2005, and then the Roche Elecsys 2010 immunoassay system, Indianapolis, IN, USA). IOPTH results were interpreted using the dual criteria,3,17 in which a baseline level drawn after induction of anesthesia is compared with a 10-minute post-resection level and an adequate drop defined as both a >50% reduction from the baseline as well as descent into the normal range. Additional IOPTH levels are sent and further exploration performed as indicated based on intraoperative findings and IOPTH results.
The median follow-up interval was 60 months (36e211), and length of follow-up did differ by group (RP 86 months [range 36e196] and CP 70.4 months [range 36e211], P ¼ .03; Table I). The mean time to RP recurrence was 77 months (range 13e170; Fig 2). Most patients had multiple calcium and PTH levels for review. At the time of recurrence, mean calcium and PTH levels were 10.8 mg/ dL (10.4e11.8) and 137.2 pg/mL (72e225), respectively. Although patients undergoing reoperation were excluded formally from the study cohort, the specific resultant anatomic data have value in delineating the observed causes of RP. To date, among the 7 of 28 RP patients who have been re-explored (1 reoperation each), mean onset of recurrence was 73.3 months (42e170) and mean interval from initial exploration to reoperative surgery was 98 months (53e196). All 7 had a single additional abnormal gland removed with restoration of eucalcemia. Of these, 4 glands were contralateral and 3 ipsilateral to the initially resected gland.
Postoperative management
Predictors of recurrence
With initial (1e2 week) postoperative calcium levels consistent with operative success, patients received 6 months of oral calcium supplementation (typically calcium carbonate 2 g BID along with a multivitamin or replacement ergocalciferol) and biochemical reevaluation at 6 months. If the 6-month evaluation determined a conventionally defined surgical cure,3 continued annual calcium screening by the referring provider was recommended. Patients
The rate of unilateral exploration did not differ by group (22 of 28, 79% RP compared with 168 of 233, 72% CP, P ¼ .7). However, all RP patients had a single gland resected at initial surgery compared with 85% of CP patients (P < .01). This would be an expected difference because the literature to date indicates that conventional RP is nearly always attributable to multiglandular disease that was unrecognized at exploration.9,18,19 We observed no difference in
Characteristics of recurrence
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Fig 1. Flow diagram of included and excluded patients.
mean resected gland weight for RP (1,261.7 mg, range 84e9,535) versus CP (1,480.6 mg, range 105e25,470), (P ¼ .7). Only 2 (0.8%) study patients had final IOPTH levels that did not meet the dual criteria to end exploration. Of note, neither has developed RP to date, with follow-up intervals of 52 months (final IOPTH of 76 pg/mL from baseline of 280 pg/mL) and 115 months (final IOPTH of 84 pg/mL from baseline of 337 pg/mL). The mean final IOPTH level was significantly higher in the RP group (49.0 pg/mL) than in the CP group (37.5 pg/mL, P < .01). In addition, patients with a final IOPTH 40 pg/mL were less likely to develop RP than those with a final IOPTH >40 pg/mL (6.2% vs 18%, P < .01; Table II). The mean 6-month calcium level was higher for RP patients (9.6 mg/dL vs 9.2 mg/dL, P ¼ .02). Patients with a 6-month
calcium level of 9.7 mg/dL were more likely to recur than those with lower levels (18% vs 4%, P ¼ .03). The mean 6-month PTH value was higher in RP patients (86.5 pg/mL vs CP 59.6 pg/ mL, P ¼ .04), and RP patients were much more likely to have eucalcemic elevation in PTH at 6 months than were CP patients (70% vs 16%, P < .01; Table II). Among patients with eucalcemic PTH elevation at 6 months, 19% have gone on to develop hypercalcemia to date. Only 20% of patients with eucalcemic PTH elevation had 25-OH vitamin D data at 6 months, and of these, 75% had normal levels. Multivariable analysis was performed and included all variables that were significant on univariable analysis. RP was independently associated with both calcium levels 9.7mg/dL (OR 6.78, P < .01) and eucalcemic PTH elevation (OR 10.02, P < .01) at 6 months.
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R. Mallick et al. / Surgery xxx (2019) 1e6 Table I Demographics of cohort patients Demographics
N (%), N ¼ 261
With cure (CP) (N ¼ 233)
With recurrence (RP) (N ¼ 28)
P value
Mean age (range), years Sex Female Male Mean peak preoperative Ca (range), mg/dL Mean peak preoperative PTH (range), pg/mL Mean duration of follow-up (range), months
60.2 (24e88)
60.2 (24e88)
59.6 (36e82)
.6 .8
214 (82%) 47 (18%) 11.48 (10.0e18.2) 170.2 (54e949) 72.1 (36e211) Median 60 months
190 (81.5%) 43 (18.5%) 11.47 (10.0e18.2) 161.1 (54e949) 70.4 (36e211)
24 (85.7%) 4 (14.3%) 11.57 (10.8e12.6) 194.4 (70e852) 86 (36e196)
.6 .4 .03
Fig 2. Kaplan-Meier curve for disease-free survival. No recurrence (solid line). Recurrence (dotted line). Lost to follow-up (hash marks).
Comparison groups were small, but there was no difference (P ¼ .9) in mean 6-month calcium levels for RP patient with recurrence before 60 months (n ¼ 12, 43%, mean Ca 9.6 mg/dL, SD 0.510), compared with recurrence more than 60 months after surgery (n ¼ 16, 57%, mean Ca 9.4 mg/dL, SD 0.592). Mean 6-month PTH levels were similar among these cohorts as well (91.2 pg/mL with recurrence < 60 months versus 86.5 months and recurrence 60 months or later, P ¼ .8). Discussion Recent advances, including development of the specialty of endocrine surgery and creation of the electronic medical record, have improved our ability to systematically follow patients longterm after parathyroidectomy. In this setting, although reported 6-month cure rates after surgical intervention for PHP remain high in the era of minimally invasive surgical approaches, new questions have arisen regarding the durability of cure.8,9 Here, in a large cohort of patients followed for a minimum of 3 years and up to 17.6 years after conventionally defined curative surgery, a surprisingly high rate of 10.7% of long-term recurrence was observed. With such long periods of eucalcemia after initial exploration (mean 77 months), the recurrences observed here are unlikely to be attributed to missed multiglandular disease but are more likely a result of de novo PHP arising in a previously normal gland. This idea is supported by the fact that each of the 7 re-explored RP patients in our study had a single additional abnormal gland removed with restoration of eucalcemia.
An important 2014 report, which set out to examine recurrence based on operative approach (seen to have no effect), instead observed an increased likelihood of recurrence associated with both a partial IOPTH drop (< 63%), and a higher 2-week postoperative PTH level (64.3 pg/mL in recurrence vs 45.3 pg/mL in cured patients).20 The median follow-up interval was 9.2 months compared with 61 months in the present cohort. A later investigation conducted by the same group examined 196 patients followed for a median of 9.2 years, with an interquartile range of 5.4 to 10.9 years, and identified younger age, double adenoma anatomy, and a <70% drop in IOPTH as potential markers for future recurrence, which occurred at the rate of 14.8% with a median onset of 6.3 years.8 By comparison, the present analysis was larger, had longer follow-up, routinely measured a 6-month PTH level, and provided multiple calcium determinations for each patient over time; however, the results again showed a high (10.7%) late recurrence rate with an onset median of 6 years. This phenomenon of late recurrence9 appears real and definitely warrants further characterization. The current findings also confirm the reported association of recurrence with the degree of postresection IOPTH descent.8,17 As have others,19,21 we found in 2014 that RP is more likely in patients with a final IOPTH level of 41 pg/mL to 65 pg/mL than with a postresection IOPTH level 40 pg/mL.17 The current findings do refine the observation by demonstrating that the cohort with lasting cure had a mean final IOPTH of 37.5 pg/mL, and the RP cohort had a higher final mean IOPTH of 49.0 pg/dL, although this association was not significant on multivariable
R. Mallick et al. / Surgery xxx (2019) 1e6
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Table II Intraoperative and postoperative characteristics of both cohorts Variable
N (%), N ¼ 261
With cure (CP) (N ¼ 233)
With recurrence (RP) (N ¼ 28)
P value
Mean gland weight (range), mg In multigland disease, the largest resected gland weight was used Type of operation Unilateral Bilateral Number of resected glands Single Multiple Mean final intraoperative PTH (range), pg/mL
1,461.8 (84e25,470)
1,480.6 (105e25,470)
1,261.7 (84e9,535)
.7
190 (72.8%) 71 (27.2%)
168 (72%) 65 (27.9%)
22 (79%) 6 (21%)
226 (86.6%) 35 (13.4%) 38.9 (8e84) IOPTH 40 pg/mL IOPTH > 40 pg/mL 9.3 (7.4e10.2) 63.2 (6.3e176) Elevated Normal or low
198 (85.0%) 35 (15.0%) 37.5 (8e84) 152 (65.2%) 81 (34.8%) 9.2 (7.4e10.2) 59.6 (6.3e176) 34 (16%) 181 (84%)
28 (100%) 0 (0%) 49.0 (17e76) 10 (35.7%) 18 (64.3%) 9.6 (8.5e10.2) 86.5 (30e160) 17 (70.8%) 7 (29.2%)
Mean 6-month serum calcium (range), mg/dL Mean 6-month intact PTH (range), pg/mL
.7
< .01
analysis. In interpreting these results, we caution surgeons that most patients (81 of 99, 82% in this study) with a final IOPTH > 40 pg/mL did not develop recurrence, but also suggest that the information may be helpful in developing cost-effective longterm surveillance recommendations. Furthermore, because all patients in the current study had conventional biochemical cure, some with late recurrence, and all who had reoperation for recurrence had an apparent de novo second adenoma with resumption of biochemical cure, it is our opinion that additional exploration at the initial operation would be unlikely to yield another abnormal gland. However, an alternative hypothesis to interpret the present findings, is that the conventional definition of cure (3) is flawed. We also evaluated potential postoperative factors associated with late recurrence. In addition to confirming that high-normal calcium levels ( 9.7 mg/dL) are indeed related to recurrence,22 we report for the first time that 6-month eucalcemic elevation of PTH is strongly associated with disease recidivism, with 19% of such patients ultimately having late recurrence. PTH elevation after parathyroidectomy is a common phenomenon that has been frequently studied, but with variable levels of ascribed significance and unclear pathophysiology that has been variously considered to be an expected response in the recovery phase, a manifestation of decreased PTH sensitivity from longstanding disease, or a sequela of vitamin D deficiency.20,23e26 Further investigation of PTH levels at 6 months postoperatively will be useful to substantiate our findings. This study has several limitations that reduce its generalizability. First, because the goal was to study patients with lengthy follow-up, although follow-up beyond 6 months is not the current standard of care, the proportion of patients with long-term surveillance >36 months in our surgical database is relatively small despite a large baseline population, and this may have skewed results to suggest a higher recurrence rate. Second, although we are intrigued by the relationship of eucalcemic PTH elevation at 6 months to vitamin D status, and the possible relationship of mildly decreased renal function to PTH elevation, these potential variables were not routinely measured until recently and thus could not be included in the present analysis. Third, albumin levels were not routinely obtained to correct the observed calcium levels, which is an additional potential confounder. Furthermore, as at any tertiary referral center, there is likely a proportion of patients who may recur yet not return for care to the institution where the index operation was performed. Finally, patients with RP had longer mean follow-up,
< .01 < .01 .02 .04 < .01
possibly planned and related to surgeon concern for recurrence, which may have skewed the results. In summary, employing a unique data set of patients who had a minimum 3 years of systematic follow-up after apparent curative parathyroidectomy for primary hyperparathyroidism, we observed a high (10.7%) long-term recurrence rate, which appears on multivariable analysis to correlate with 6-month calcium levels of 9.7 mg/dL and with the novel factor of eucalcemic elevation in PTH at 6 months. Although not all patients with these findings will go on to recur, the data suggest that, for such patients, counseling regarding careful adherence to recommended follow-up, including annual serum calcium levels, is prudent. Funding/Support The authors have no external funding sources to report. Conflict of interest/Disclosure The authors have no conflicts of interest to disclose. References 1. Adler JT, Sippel RS, Chen H. New trends in parathyroid surgery. Curr Probl Surg. 2010;47:958e1017. 2. Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: A “forme fruste” of an old disease. J Clin Endocrinol Metab. 2003;88:5348e5352. 3. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959e968. 4. Aliabadi-Wahle S, Kelly TL, Rozenfeld Y, et al. Treatment strategies for primary hyperparathyroidism: What is the cost? Am Surg. 2014;80:1146e1151. 5. Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg. 2011;253:585e591. 6. Allendorf J, DiGorgi M, Spanknebel K, Inabnet W, Chabot J, Logerfo P. 1112 consecutive bilateral neck explorations for primary hyperparathyroidism. World J Surg. 2007;31:2075e2080. 7. Udelsman R. Approach to the patient with persistent or recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2011;96:2950e2958. 8. Lou I, Balentine C, Clarkson S, Schneider DF, Sippel RS, Chen H. How long should we follow patients after apparently curative parathyroidectomy? Surgery. 2017;161:54e61. 9. Pasieka JL. What should we tell our patients? Lifetime guarantee or is it 5- to 10-year warranty on a parathyroidectomy for primary hyperparathyroidism? World J Surg. 2015;39:1928e1929. 10. Yu N, Leese GP, Smith D, Donnan PT. The natural history of treated and untreated primary hyperparathyroidism: The parathyroid epidemiology and audit research study. QJM. 2011;104:513e521.
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11. Hedback G, Oden A. Recurrence of hyperparathyroidism; A long-term follow-up after surgery for primary hyperparathyroidism. Eur J Endocrinol. 2003;148: 413e421. 12. Hodin R, Angelos P, Carty S, et al. No need to abandon unilateral parathyroid surgery. J Am Coll Surg. 2012;215:297; author reply 297e300. 13. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery. 1994;116:954e957; discussion 957e958. 14. Richards ML, Thompson GB, Farley DR, Grant CS. Reoperative parathyroidectomy in 228 patients during the era of minimal-access surgery and intraoperative parathyroid hormone monitoring. Am J Surg. 2008;196: 937e942; discussion 942e943. 15. Miccoli P, Pinchera A, Cecchini G, et al. Minimally invasive, video-assisted parathyroid surgery for primary hyperparathyroidism. J Endocrinol Invest. 1997;20:429e430. 16. Melck AL, Armstrong MJ, Yip L, Carty SE. Case-controlled comparison of videoassisted and conventional minimally invasive parathyroidectomy. Am Surg. 2012;78:125e132. 17. Wharry LI, Yip L, Armstrong MJ, et al. The final intraoperative parathyroid hormone level: How low should it go? World J Surg. 2014 Mar;38(3):558e563. 18. Norman J, Lopez J, Politz D. Abandoning unilateral parathyroidectomy: Why we reversed our position after 15,000 parathyroid operations. J Am Coll Surg. 2012;214:260e269. 19. Rajaei MH, Bentz AM, Schneider DF, Sippel RS, Chen H, Oltmann SC. Justified follow-up: A final intraoperative parathyroid hormone (ioPTH) over 40 pg/mL
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is associated with an increased risk of persistence and recurrence in primary hyperparathyroidism. Ann Surg Oncol. 2015;22:454e459. Schneider DF, Mazeh H, Chen H, Sippel RS. Predictors of recurrence in primary hyperparathyroidism: An analysis of 1386 cases. Ann Surg. 2014;259: 563e568. Heller KS, Blumberg SN. Relation of final intraoperative parathyroid hormone level and outcome following parathyroidectomy. Arch Otolaryngol Head Neck Surg. 2009;135:1103e1107. Wang TS, Ostrower ST, Heller KS. Persistently elevated parathyroid hormone levels after parathyroid surgery. Surgery. 2005;138:1130e1135; discussion 1135e1136. Mittendorf EA, McHenry CR. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. Arch Otolaryngol Head Neck Surg. 2002;128:275e279. Carsello CB, Yen TW, Wang TS. Persistent elevation in serum parathyroid hormone levels in normocalcemic patients after parathyroidectomy: Does it matter? Surgery. 2012;152:575e581; discussion 581e583. Solorzano CC, Mendez W, Lew JI, et al. Long-term outcome of patients with elevated parathyroid hormone levels after successful parathyroidectomy for sporadic primary hyperparathyroidism. Arch Surg. 2008;143:659e663; discussion 663. Goldfarb M, Gondek S, Irvin 3rd GL, Lew JI. Normocalcemic parathormone elevation after successful parathyroidectomy: Long-term analysis of parathormone variations over 10 years. Surgery. 2011;150:1076e1084.
Discussion Dr Erin Felger (Washington, DC): I just have 2 questions for you. Was there any documentation during the first procedure that the other parathyroid on the same side had been identified and found to be normal? That’s number 1. Subsequent to that, was a full exploration considered or were full explorations done for the second operation? At that point, when you are going back in again, I am just curious as to what your thought process would be in terms of making sure that you are not missing any other glands, particularly when you have two on the same side, as in your test case. Dr Reema Mallick: With respect to this particular case, I know the first exploration was a focused one. So, the ipsilateral gland was not identified, given the appropriate IOPTH drop. With respect to your second question, it was a focused unilateral exploration. As we know, reoperative parathyroidectomies are always a bit trickier. There’s scar tissue, and some previous planes have been violated. So, generally, if we had the opportunity to make it a more focused approach and it appears to be curative, we don’t go over to the contralateral side. Dr Electron Kebebew (Palo Alto, CA): Nice work and presentation, Dr Mallick. I have a question and a suggestion for you. For the patients who had recurrent disease, did you do genetic testing? Did they have MEN1, MEN4, or isolated familial hyperparathyroidism? I’ll let you answer that first. Dr Reema Mallick: For all patients that recurred, we went back through their records and made sure that there wasn’t something missed. Certainly, there were patients in our database who appeared to have persistent disease or had other issues suggesting they needed to undergo mutational testing for either familial hypocaliuric hypercalcemia or MEN. But we believe that none of the
patients in the recurrent cohort were patients who had any indication of genetic disease. Dr Electron Kebebew: Well, they should be tested. If they have recurrent disease, it’s inherited until proven otherwise. So, I encourage you that all of these patients should get genetic testing. Also, I suggest that your conclusion should be that the definition of a normal postoperative calcium and an elevated PTH should not indicate that the patient is cured, but that they have persistent disease. What are your thoughts on that? Dr Reema Mallick: Yes, I think we thought a lot about the point that you raise as far as how we should define cure after surgery and if we should even use the term “cure.” Perhaps there is a less rigid definition that would allow for the possibility that up to 10% of these patients later recur. Dr Sareh Prangi (Boston, MA): I have a question about your second operation and what you found as far as the intraoperative final PTH level for these patients. Because if it’s elevated, it would hint that perhaps it’s just a second adenoma, but it is, in fact, multigland disease, and in another X percent you will be doing a third operation down the road. Dr Reema Mallick: Obviously, it’s a very small group of patients that were subsequently re-explored. I imagine that is certainly a possibility that may arise if we were to take all of these patients back to the operating room. The bar is higher for patients who undergo reoperation in our practice. Most of these patients will either have positive imaging or very significant manifestations of the disease. In our group of seven, we suggest that all these patients have been cured subsequently with their second exploration and resection of the second adenoma.
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Factors associated with late recurrence after parathyroidectomy for primary hyperparathyroidism Reema Mallick, MD, Kristina J. Nicholson, MD, Linwah Yip, MD, Sally E. Carty, MD, Kelly L. McCoy, MD* Division of Endocrine Surgery, Department of Surgery, University of Pittsburgh Medical Center, PA
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 1 May 2019 Available online xxx
Background: A recent study with unusually lengthy follow-up after surgery for primary hyperparathyroidism reported higher recurrence rates than previously appreciated. We sought to identify specific factors associated with late recurrence after seemingly curative parathyroidectomy. Methods: Prospectively collected data were retrieved for patients who had surgical treatment of sporadic primary hyperparathyroidism with 3-year follow-up (3e17.6 years). Recurrence was defined by 6 months of eucalcemia with subsequent hypercalcemia and a high or unsuppressed parathyroid hormone. Recurrent patients were compared with cured patients (defined by consistent eucalcemia). Results: Among 261 patients, 28 (10.7%) had recurrence and 233 (89.3%) were cured. The mean time to recurrence was 77 months (range 13e170). The mean final intraoperative parathyroid hormone (49.0 pg/mL vs 37.5 pg/mL, P < .01), 6-month calcium levels (9.6 mg/dL vs 9.2 mg/dL, P ¼ .02) and mean 6-month parathyroid hormone levels (86.5 pg/mL vs 59.6 pg/mL, P ¼ .04) were higher for recurrence. By multivariable analysis, 6-month calcium 9.7 and eucalcemic elevation of the parathyroid hormone at 6 months were independently associated with recurrent primary hyperparathyroidism. Conclusion: Long-term follow-up after apparent curative surgery for primary hyperparathyroidism identified a high late recurrence rate (10.7%), up to 17 years later. A 6-month calcium >9.7 mg/dL and eucalcemic parathyroid hormone elevation at 6 months may be associated with recurrence, and such findings may help guide management. © 2019 Published by Elsevier Inc.
Introduction Primary hyperparathyroidism (PHP) is an increasingly common endocrinopathy with a minimum of 100,000 new cases in the United States annually.1 Most patients are detected incidentally on routine biochemical testing.2 Failure to treat affected patients leads to increased risk for renal, bone, and cardiovascular disease, and decreased quality of life, which ultimately results in greater healthcare costs.3,4 Surgical extirpation is the only curative treatment for PHP, and cure rates have been routinely described in excess of 95% in the hands of experienced, high-volume surgeons.3,5,6
Presented at the 2019 Annual Meeting of the American Association of Endocrine Surgeons. * Reprint requests: Kelly L. McCoy, MD, Division of Endocrine Surgery, 3471 Fifth Ave, Suite 100, Kaufmann Building, Pittsburgh, PA, 15213. E-mail address: [email protected] (K.L. McCoy). https://doi.org/10.1016/j.surg.2019.05.076 0039-6060/© 2019 Published by Elsevier Inc.
For decades, cure in hyperparathyroidism has been defined as restoration of eucalcemia for a minimum of 6 months postoperatively.3,7 However, the durability of surgical cure long term was recently challenged by a report that longer length of followup may yield higher rates of late failure. In a single-institution study of 196 patients who were biochemically cured at > 6 months with subsequent follow-up for 5.4 to 10.9 years (median 9.2 y), there was a 14.8% relapse rate,8 in stark contrast to historical data sets.3,9e12 Recurrent PHP is a challenging problem for both patients and providers because those effected continue to be at risk for the symptoms and associated morbidities of PHP. Moreover, attempts at cure in the reoperative setting have higher costs and risks, including operative failure.3,13,14 In a large, long-term single-institution study, we aimed to determine the rate and pattern of onset for recurrence and to identify novel associated factors that may affect management, particularly in early postoperative surveillance.
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Methods Study design Using an institutionally approved (QI#1651) parathyroid database, prospectively collected clinical data were retrieved for all patients who underwent initial surgery for sporadic PHP from November 1995 to January 2015 with long-term follow-up, defined as >36 months of postoperative biochemical evaluation. Patients were then excluded if they underwent concomitant thyroidectomy, had parathyroid exploration without use of intraoperative parathyroid hormone (IOPTH) monitoring, had hypercalcemia within 6 months of surgery (persistent PHP), or had parathyroid cancer. Cure was defined by eucalcemia at 6 months after surgery. Long-term cure of primary hyperparathyroidism (CP) was defined by consistent eucalcemia for at least 3 years, through the most recent date of follow-up. Recurrent disease (RP) was defined by postoperative eucalcemia at 6 months, with subsequent hypercalcemia plus high or inappropriately unsuppressed parathyroid hormone (PTH) levels. To compare the CP and RP groups, demographic and perioperative data, including operative conduct; number of glands resected; gland weight; and IOPTH results, including percentage decline from baseline value, were extracted from the database. All charts for patients with suspected RP were carefully reviewed to confirm biochemical recurrence and the specific timing of calcium and PTH elevation, including calcium, 25-OH Vitamin D, and intact PTH at 6 months and afterward; total duration of follow-up; and time to recurrence, if applicable. All available calcium and PTH levels were reviewed for the duration of follow-up. Preoperative evaluation and surgical management
who appeared at any time to have RP routinely received detailed evaluation either by endocrinology or endocrine surgery to exclude confounding diagnoses and conduct surveillance long term. Statistical analysis Statistical analysis included use of Student’s t test for evaluation of continuous data and the Fisher exact test for categorical data. Association with PHP recurrence was assessed using logistic regression (Stata SE, v 14.0, StataCorp, College Station, TX, USA). A P value <.05 was considered significant. Results Patient characteristics Of patients who had surgery for PHP during the study period, 261 met inclusion criteria (Fig 1), 82% were women, and the mean age was 60.2 years (range 24e88). A total of 28 patients (10.7%) had RP and 233 (89.3%) had CP. Gender (RP 85.7% women versus CP 81.5%, P ¼ .8) and mean age (RP 59.6 years versus CP 60.2 years, P ¼ .6) were similar between groups. The mean highest preoperative calcium level was similar for RP (11.57 mg/dL, SD 0.520) and CP (11.47 mg/dL, SD 0.992) patients (P ¼ .6), and the mean highest preoperative PTH level was not significantly different (RP 194.4 pg/ mL, SD 182.8 versus CP 161.1 pg/mL, SD 130.8; P ¼ .4). Preoperatively, 94% of patients had both calcium and PTH levels concurrently above the upper limit of normal, as presented in Table I. High normal calcium levels were present in 10 patients (10 mg/dL to <10.2 mg/dL) along with PTH levels > 65 pg/mL, and these cases (3.8%) can be classified as normocalcemic PHP. In addition, 5 patients had inappropriately unsuppressed PTH levels from 54 to 63.8 (high normal 65 pg/mL) with concurrently elevated calcium levels (10.9 mg/dLe11.6 mg/dL). In this study there were no observed cases of permanent hypoparathyroidism or permanent recurrent laryngeal nerve dysfunction complicating surgery.
For all patients, the diagnosis of PHP was reached biochemically.3 Before operative intervention, imaging studies were performed using the optimal modality available at the time. In brief, we used 99mTc-sestamibi until 1997, used Sestamibi-SPECT from 1997 to 2010, added routine ultrasound in 2005, and used SPECT-CT plus ultrasound from 2010 to the present. Based on preoperative evaluation and guided by intraoperative findings and IOPTH results, patients underwent unilateral or bilateral exploration under general or cervical block anesthesia, and beginning in 2004 for selected patients, a video-assisted minimally invasive approach was used.15,16 Resected parathyroid tissue was routinely weighed, and tissue identity was typically confirmed by either frozen section analysis or intraoperative PTH tissue aspirate. Routine IOPTH monitoring was implemented in 1995 (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA until 2005, and then the Roche Elecsys 2010 immunoassay system, Indianapolis, IN, USA). IOPTH results were interpreted using the dual criteria,3,17 in which a baseline level drawn after induction of anesthesia is compared with a 10-minute post-resection level and an adequate drop defined as both a >50% reduction from the baseline as well as descent into the normal range. Additional IOPTH levels are sent and further exploration performed as indicated based on intraoperative findings and IOPTH results.
The median follow-up interval was 60 months (36e211), and length of follow-up did differ by group (RP 86 months [range 36e196] and CP 70.4 months [range 36e211], P ¼ .03; Table I). The mean time to RP recurrence was 77 months (range 13e170; Fig 2). Most patients had multiple calcium and PTH levels for review. At the time of recurrence, mean calcium and PTH levels were 10.8 mg/ dL (10.4e11.8) and 137.2 pg/mL (72e225), respectively. Although patients undergoing reoperation were excluded formally from the study cohort, the specific resultant anatomic data have value in delineating the observed causes of RP. To date, among the 7 of 28 RP patients who have been re-explored (1 reoperation each), mean onset of recurrence was 73.3 months (42e170) and mean interval from initial exploration to reoperative surgery was 98 months (53e196). All 7 had a single additional abnormal gland removed with restoration of eucalcemia. Of these, 4 glands were contralateral and 3 ipsilateral to the initially resected gland.
Postoperative management
Predictors of recurrence
With initial (1e2 week) postoperative calcium levels consistent with operative success, patients received 6 months of oral calcium supplementation (typically calcium carbonate 2 g BID along with a multivitamin or replacement ergocalciferol) and biochemical reevaluation at 6 months. If the 6-month evaluation determined a conventionally defined surgical cure,3 continued annual calcium screening by the referring provider was recommended. Patients
The rate of unilateral exploration did not differ by group (22 of 28, 79% RP compared with 168 of 233, 72% CP, P ¼ .7). However, all RP patients had a single gland resected at initial surgery compared with 85% of CP patients (P < .01). This would be an expected difference because the literature to date indicates that conventional RP is nearly always attributable to multiglandular disease that was unrecognized at exploration.9,18,19 We observed no difference in
Characteristics of recurrence
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Fig 1. Flow diagram of included and excluded patients.
mean resected gland weight for RP (1,261.7 mg, range 84e9,535) versus CP (1,480.6 mg, range 105e25,470), (P ¼ .7). Only 2 (0.8%) study patients had final IOPTH levels that did not meet the dual criteria to end exploration. Of note, neither has developed RP to date, with follow-up intervals of 52 months (final IOPTH of 76 pg/mL from baseline of 280 pg/mL) and 115 months (final IOPTH of 84 pg/mL from baseline of 337 pg/mL). The mean final IOPTH level was significantly higher in the RP group (49.0 pg/mL) than in the CP group (37.5 pg/mL, P < .01). In addition, patients with a final IOPTH 40 pg/mL were less likely to develop RP than those with a final IOPTH >40 pg/mL (6.2% vs 18%, P < .01; Table II). The mean 6-month calcium level was higher for RP patients (9.6 mg/dL vs 9.2 mg/dL, P ¼ .02). Patients with a 6-month
calcium level of 9.7 mg/dL were more likely to recur than those with lower levels (18% vs 4%, P ¼ .03). The mean 6-month PTH value was higher in RP patients (86.5 pg/mL vs CP 59.6 pg/ mL, P ¼ .04), and RP patients were much more likely to have eucalcemic elevation in PTH at 6 months than were CP patients (70% vs 16%, P < .01; Table II). Among patients with eucalcemic PTH elevation at 6 months, 19% have gone on to develop hypercalcemia to date. Only 20% of patients with eucalcemic PTH elevation had 25-OH vitamin D data at 6 months, and of these, 75% had normal levels. Multivariable analysis was performed and included all variables that were significant on univariable analysis. RP was independently associated with both calcium levels 9.7mg/dL (OR 6.78, P < .01) and eucalcemic PTH elevation (OR 10.02, P < .01) at 6 months.
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R. Mallick et al. / Surgery xxx (2019) 1e6 Table I Demographics of cohort patients Demographics
N (%), N ¼ 261
With cure (CP) (N ¼ 233)
With recurrence (RP) (N ¼ 28)
P value
Mean age (range), years Sex Female Male Mean peak preoperative Ca (range), mg/dL Mean peak preoperative PTH (range), pg/mL Mean duration of follow-up (range), months
60.2 (24e88)
60.2 (24e88)
59.6 (36e82)
.6 .8
214 (82%) 47 (18%) 11.48 (10.0e18.2) 170.2 (54e949) 72.1 (36e211) Median 60 months
190 (81.5%) 43 (18.5%) 11.47 (10.0e18.2) 161.1 (54e949) 70.4 (36e211)
24 (85.7%) 4 (14.3%) 11.57 (10.8e12.6) 194.4 (70e852) 86 (36e196)
.6 .4 .03
Fig 2. Kaplan-Meier curve for disease-free survival. No recurrence (solid line). Recurrence (dotted line). Lost to follow-up (hash marks).
Comparison groups were small, but there was no difference (P ¼ .9) in mean 6-month calcium levels for RP patient with recurrence before 60 months (n ¼ 12, 43%, mean Ca 9.6 mg/dL, SD 0.510), compared with recurrence more than 60 months after surgery (n ¼ 16, 57%, mean Ca 9.4 mg/dL, SD 0.592). Mean 6-month PTH levels were similar among these cohorts as well (91.2 pg/mL with recurrence < 60 months versus 86.5 months and recurrence 60 months or later, P ¼ .8). Discussion Recent advances, including development of the specialty of endocrine surgery and creation of the electronic medical record, have improved our ability to systematically follow patients longterm after parathyroidectomy. In this setting, although reported 6-month cure rates after surgical intervention for PHP remain high in the era of minimally invasive surgical approaches, new questions have arisen regarding the durability of cure.8,9 Here, in a large cohort of patients followed for a minimum of 3 years and up to 17.6 years after conventionally defined curative surgery, a surprisingly high rate of 10.7% of long-term recurrence was observed. With such long periods of eucalcemia after initial exploration (mean 77 months), the recurrences observed here are unlikely to be attributed to missed multiglandular disease but are more likely a result of de novo PHP arising in a previously normal gland. This idea is supported by the fact that each of the 7 re-explored RP patients in our study had a single additional abnormal gland removed with restoration of eucalcemia.
An important 2014 report, which set out to examine recurrence based on operative approach (seen to have no effect), instead observed an increased likelihood of recurrence associated with both a partial IOPTH drop (< 63%), and a higher 2-week postoperative PTH level (64.3 pg/mL in recurrence vs 45.3 pg/mL in cured patients).20 The median follow-up interval was 9.2 months compared with 61 months in the present cohort. A later investigation conducted by the same group examined 196 patients followed for a median of 9.2 years, with an interquartile range of 5.4 to 10.9 years, and identified younger age, double adenoma anatomy, and a <70% drop in IOPTH as potential markers for future recurrence, which occurred at the rate of 14.8% with a median onset of 6.3 years.8 By comparison, the present analysis was larger, had longer follow-up, routinely measured a 6-month PTH level, and provided multiple calcium determinations for each patient over time; however, the results again showed a high (10.7%) late recurrence rate with an onset median of 6 years. This phenomenon of late recurrence9 appears real and definitely warrants further characterization. The current findings also confirm the reported association of recurrence with the degree of postresection IOPTH descent.8,17 As have others,19,21 we found in 2014 that RP is more likely in patients with a final IOPTH level of 41 pg/mL to 65 pg/mL than with a postresection IOPTH level 40 pg/mL.17 The current findings do refine the observation by demonstrating that the cohort with lasting cure had a mean final IOPTH of 37.5 pg/mL, and the RP cohort had a higher final mean IOPTH of 49.0 pg/dL, although this association was not significant on multivariable
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Table II Intraoperative and postoperative characteristics of both cohorts Variable
N (%), N ¼ 261
With cure (CP) (N ¼ 233)
With recurrence (RP) (N ¼ 28)
P value
Mean gland weight (range), mg In multigland disease, the largest resected gland weight was used Type of operation Unilateral Bilateral Number of resected glands Single Multiple Mean final intraoperative PTH (range), pg/mL
1,461.8 (84e25,470)
1,480.6 (105e25,470)
1,261.7 (84e9,535)
.7
190 (72.8%) 71 (27.2%)
168 (72%) 65 (27.9%)
22 (79%) 6 (21%)
226 (86.6%) 35 (13.4%) 38.9 (8e84) IOPTH 40 pg/mL IOPTH > 40 pg/mL 9.3 (7.4e10.2) 63.2 (6.3e176) Elevated Normal or low
198 (85.0%) 35 (15.0%) 37.5 (8e84) 152 (65.2%) 81 (34.8%) 9.2 (7.4e10.2) 59.6 (6.3e176) 34 (16%) 181 (84%)
28 (100%) 0 (0%) 49.0 (17e76) 10 (35.7%) 18 (64.3%) 9.6 (8.5e10.2) 86.5 (30e160) 17 (70.8%) 7 (29.2%)
Mean 6-month serum calcium (range), mg/dL Mean 6-month intact PTH (range), pg/mL
.7
< .01
analysis. In interpreting these results, we caution surgeons that most patients (81 of 99, 82% in this study) with a final IOPTH > 40 pg/mL did not develop recurrence, but also suggest that the information may be helpful in developing cost-effective longterm surveillance recommendations. Furthermore, because all patients in the current study had conventional biochemical cure, some with late recurrence, and all who had reoperation for recurrence had an apparent de novo second adenoma with resumption of biochemical cure, it is our opinion that additional exploration at the initial operation would be unlikely to yield another abnormal gland. However, an alternative hypothesis to interpret the present findings, is that the conventional definition of cure (3) is flawed. We also evaluated potential postoperative factors associated with late recurrence. In addition to confirming that high-normal calcium levels ( 9.7 mg/dL) are indeed related to recurrence,22 we report for the first time that 6-month eucalcemic elevation of PTH is strongly associated with disease recidivism, with 19% of such patients ultimately having late recurrence. PTH elevation after parathyroidectomy is a common phenomenon that has been frequently studied, but with variable levels of ascribed significance and unclear pathophysiology that has been variously considered to be an expected response in the recovery phase, a manifestation of decreased PTH sensitivity from longstanding disease, or a sequela of vitamin D deficiency.20,23e26 Further investigation of PTH levels at 6 months postoperatively will be useful to substantiate our findings. This study has several limitations that reduce its generalizability. First, because the goal was to study patients with lengthy follow-up, although follow-up beyond 6 months is not the current standard of care, the proportion of patients with long-term surveillance >36 months in our surgical database is relatively small despite a large baseline population, and this may have skewed results to suggest a higher recurrence rate. Second, although we are intrigued by the relationship of eucalcemic PTH elevation at 6 months to vitamin D status, and the possible relationship of mildly decreased renal function to PTH elevation, these potential variables were not routinely measured until recently and thus could not be included in the present analysis. Third, albumin levels were not routinely obtained to correct the observed calcium levels, which is an additional potential confounder. Furthermore, as at any tertiary referral center, there is likely a proportion of patients who may recur yet not return for care to the institution where the index operation was performed. Finally, patients with RP had longer mean follow-up,
< .01 < .01 .02 .04 < .01
possibly planned and related to surgeon concern for recurrence, which may have skewed the results. In summary, employing a unique data set of patients who had a minimum 3 years of systematic follow-up after apparent curative parathyroidectomy for primary hyperparathyroidism, we observed a high (10.7%) long-term recurrence rate, which appears on multivariable analysis to correlate with 6-month calcium levels of 9.7 mg/dL and with the novel factor of eucalcemic elevation in PTH at 6 months. Although not all patients with these findings will go on to recur, the data suggest that, for such patients, counseling regarding careful adherence to recommended follow-up, including annual serum calcium levels, is prudent. Funding/Support The authors have no external funding sources to report. Conflict of interest/Disclosure The authors have no conflicts of interest to disclose. References 1. Adler JT, Sippel RS, Chen H. New trends in parathyroid surgery. Curr Probl Surg. 2010;47:958e1017. 2. Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: A “forme fruste” of an old disease. J Clin Endocrinol Metab. 2003;88:5348e5352. 3. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151:959e968. 4. Aliabadi-Wahle S, Kelly TL, Rozenfeld Y, et al. Treatment strategies for primary hyperparathyroidism: What is the cost? Am Surg. 2014;80:1146e1151. 5. Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg. 2011;253:585e591. 6. Allendorf J, DiGorgi M, Spanknebel K, Inabnet W, Chabot J, Logerfo P. 1112 consecutive bilateral neck explorations for primary hyperparathyroidism. World J Surg. 2007;31:2075e2080. 7. Udelsman R. Approach to the patient with persistent or recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2011;96:2950e2958. 8. Lou I, Balentine C, Clarkson S, Schneider DF, Sippel RS, Chen H. How long should we follow patients after apparently curative parathyroidectomy? Surgery. 2017;161:54e61. 9. Pasieka JL. What should we tell our patients? Lifetime guarantee or is it 5- to 10-year warranty on a parathyroidectomy for primary hyperparathyroidism? World J Surg. 2015;39:1928e1929. 10. Yu N, Leese GP, Smith D, Donnan PT. The natural history of treated and untreated primary hyperparathyroidism: The parathyroid epidemiology and audit research study. QJM. 2011;104:513e521.
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11. Hedback G, Oden A. Recurrence of hyperparathyroidism; A long-term follow-up after surgery for primary hyperparathyroidism. Eur J Endocrinol. 2003;148: 413e421. 12. Hodin R, Angelos P, Carty S, et al. No need to abandon unilateral parathyroid surgery. J Am Coll Surg. 2012;215:297; author reply 297e300. 13. Doherty GM, Weber B, Norton JA. Cost of unsuccessful surgery for primary hyperparathyroidism. Surgery. 1994;116:954e957; discussion 957e958. 14. Richards ML, Thompson GB, Farley DR, Grant CS. Reoperative parathyroidectomy in 228 patients during the era of minimal-access surgery and intraoperative parathyroid hormone monitoring. Am J Surg. 2008;196: 937e942; discussion 942e943. 15. Miccoli P, Pinchera A, Cecchini G, et al. Minimally invasive, video-assisted parathyroid surgery for primary hyperparathyroidism. J Endocrinol Invest. 1997;20:429e430. 16. Melck AL, Armstrong MJ, Yip L, Carty SE. Case-controlled comparison of videoassisted and conventional minimally invasive parathyroidectomy. Am Surg. 2012;78:125e132. 17. Wharry LI, Yip L, Armstrong MJ, et al. The final intraoperative parathyroid hormone level: How low should it go? World J Surg. 2014 Mar;38(3):558e563. 18. Norman J, Lopez J, Politz D. Abandoning unilateral parathyroidectomy: Why we reversed our position after 15,000 parathyroid operations. J Am Coll Surg. 2012;214:260e269. 19. Rajaei MH, Bentz AM, Schneider DF, Sippel RS, Chen H, Oltmann SC. Justified follow-up: A final intraoperative parathyroid hormone (ioPTH) over 40 pg/mL
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Discussion Dr Erin Felger (Washington, DC): I just have 2 questions for you. Was there any documentation during the first procedure that the other parathyroid on the same side had been identified and found to be normal? That’s number 1. Subsequent to that, was a full exploration considered or were full explorations done for the second operation? At that point, when you are going back in again, I am just curious as to what your thought process would be in terms of making sure that you are not missing any other glands, particularly when you have two on the same side, as in your test case. Dr Reema Mallick: With respect to this particular case, I know the first exploration was a focused one. So, the ipsilateral gland was not identified, given the appropriate IOPTH drop. With respect to your second question, it was a focused unilateral exploration. As we know, reoperative parathyroidectomies are always a bit trickier. There’s scar tissue, and some previous planes have been violated. So, generally, if we had the opportunity to make it a more focused approach and it appears to be curative, we don’t go over to the contralateral side. Dr Electron Kebebew (Palo Alto, CA): Nice work and presentation, Dr Mallick. I have a question and a suggestion for you. For the patients who had recurrent disease, did you do genetic testing? Did they have MEN1, MEN4, or isolated familial hyperparathyroidism? I’ll let you answer that first. Dr Reema Mallick: For all patients that recurred, we went back through their records and made sure that there wasn’t something missed. Certainly, there were patients in our database who appeared to have persistent disease or had other issues suggesting they needed to undergo mutational testing for either familial hypocaliuric hypercalcemia or MEN. But we believe that none of the
patients in the recurrent cohort were patients who had any indication of genetic disease. Dr Electron Kebebew: Well, they should be tested. If they have recurrent disease, it’s inherited until proven otherwise. So, I encourage you that all of these patients should get genetic testing. Also, I suggest that your conclusion should be that the definition of a normal postoperative calcium and an elevated PTH should not indicate that the patient is cured, but that they have persistent disease. What are your thoughts on that? Dr Reema Mallick: Yes, I think we thought a lot about the point that you raise as far as how we should define cure after surgery and if we should even use the term “cure.” Perhaps there is a less rigid definition that would allow for the possibility that up to 10% of these patients later recur. Dr Sareh Prangi (Boston, MA): I have a question about your second operation and what you found as far as the intraoperative final PTH level for these patients. Because if it’s elevated, it would hint that perhaps it’s just a second adenoma, but it is, in fact, multigland disease, and in another X percent you will be doing a third operation down the road. Dr Reema Mallick: Obviously, it’s a very small group of patients that were subsequently re-explored. I imagine that is certainly a possibility that may arise if we were to take all of these patients back to the operating room. The bar is higher for patients who undergo reoperation in our practice. Most of these patients will either have positive imaging or very significant manifestations of the disease. In our group of seven, we suggest that all these patients have been cured subsequently with their second exploration and resection of the second adenoma.