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Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: A 2-institution experience
Intraoperative parathyroid hormone monitoring fails to detect double parathyroid adenomas: A 2-institution experience Paul G. Gauger, MD, Gaurav Agarwal, MD, Barry G. England, PhD, Leigh W. Delbridge, MD, Keith A. Matz, BS, MT (ASCP), Margaret Wilkinson, MD, Bruce G. Robinson, MD, and Norman W. Thompson, MD, Ann Arbor, Mich, and Sydney, New South Wales, Australia
Background. We hypothesized that intraoperative parathyroid hormone monitoring (IOPTH) reliably would detect double parathyroid adenomas. Methods. This was a retrospective study of 20 patients undergoing conventional parathyroidectomy with resection of exactly 2 abnormal glands. Full exploration was performed regardless of IOPTH values, which were measured after anesthetic induction and 5 and 10 minutes following removal of the first abnormal parathyroid gland. Failure to fall below 50% of baseline value by 10 minutes following resection of the first gland indicated the presence of multiglandular disease. Results. All patients were cured. All excised glands were hypercellular on histology. Mean IOPTH values in 9 of the 20 patients with true negative results (noncurative decrease, another gland present) were 66% ± 7% at 5 minutes and 83% ± 15% at 10 minutes. The IOPTH values in 11 of the 20 patients with false positive results (curative decrease, another gland present) were 28% ± 4% at 5 minutes and 18% ± 2% at 10 minutes. The false positive rate of IOPTH was 55%. Conclusions. We found that IOPTH failed to reliably detect the presence of double parathyroid adenomas. These data suggest that caution should be exercised when terminating limited parathyroid exploration based on a curative fall in IOPTH values. (Surgery 2001;130:1005-10.) From the University of Michigan Departments of Surgery and Pathology, Ann Arbor, Mich, and the Royal North Shore Hospital Departments of Surgery and Endocrinology, Sydney, New South Wales, Australia
INTRAOPERATIVE PARATHYROID HORMONE MONITORING (IOPTH) has been used to facilitate successful parathyroidectomy including minimally invasive techniques. Experience is rapidly accruing with this adjunctive technology and it is likely that it will remain an integral part of parathyroid surgery in the future. Endocrine surgeons still are learning the limits of the assay’s application to specific clinical situations, however. The technology may be changing the way in which we think about the pathophysiology of the different variants of hyperparathyroidism. The recognition of multiglandular disease is a facet of parathyroid surgery that Presented at the 22nd Annual Meeting of the American Association of Endocrine Surgeons, Atlanta, Ga, April 28-May 1, 2001. Reprint requests: Paul G. Gauger, MD, Assistant Professor of Surgery, University of Michigan Hospital, Department of Surgery—Division of Endocrine Surgery, 1500 E Medical Center Dr, TC 2920H, Ann Arbor, MI 48109-0331. Copyright © 2001 by Mosby, Inc. 0039-6060/2001/$35.00 + 0 11/6/118385 doi:10.1067/msy.2001.118385
continues as a problem with an imperfect solution. One proposed use of IOPTH is its ability to detect multiglandular disease allowing extension of the operation and ensuring cure of hyperparathyroidism, an issue especially relevant to minimally invasive parathyroidectomy techniques. Our hypothesis was that IOPTH consistently would predict the presence of multiglandular disease, specifically double parathyroid adenomas, which may be a cause of failed initial cervical exploration. The question asked with this study was whether excision of the first of 2 abnormal parathyroid glands consistently was associated with a noncurative fall in IOPTH values, suggesting the presence of the second abnormal parathyroid gland. METHODS This was a retrospective, multinational, 2-institution study of 20 patients treated from October 1999 through November 2000 at the University of Michigan Hospital in Ann Arbor, Mich, and the Royal North Shore Hospital in Sydney, Australia. During this defined time period, a combined total SURGERY 1005
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of 457 patients underwent parathyroidectomy at both institutions. The incidence of recognized double adenoma in these patients was 4.4%. All patients were treated as intended with a bilateral open parathyroid exploration, and the study group did not include patients undergoing minimally invasive parathyroidectomy because the existence of double adenoma could not otherwise be confirmed. Patients undergoing reoperation for persistent or recurrent hyperparathyroidism were not included. Each patient had exactly 2 abnormal parathyroid glands excised, and patients with recognized parathyroid hyperplasia were not included. The determination of an abnormal parathyroid gland was made on gross morphologic criteria, principally size greater than 70 mg estimated mass. During open parathyroidectomy, IOPTH values were measured at post-induction baseline and at 5 and 10 minutes following removal of the first abnormal parathyroid gland. Full parathyroid exploration was performed in all patients regardless of IOPTH values. In all cases, continued exploration revealed 1 other abnormal parathyroid gland that subsequently was removed. Biopsy of normal parathyroid glands was not performed routinely. Both institutions used the Immulite System (Diagnostic Products Corporation, Los Angeles, Calif). A fall of IOPTH values to less than or equal to 50% of baseline at 10 minutes following excision of the first gland was considered to indicate biochemical cure. Statistical analysis was performed using analysis of variance and independent t- tests, and the data below are expressed as mean ± standard error of the mean. What follows is an explanation of 4 terms as they apply in context to this study: 1) true positive, 2) false negative, 3) false positive, and 4) true negative. In the common situation in which only a single adenoma exists and is excised with a curative fall in IOPTH values (PTH ≤ 50% of baseline at 10 minutes after excision) and the patient is cured, this is a true positive result. In the situation in which a single adenoma exists and is excised with a noncurative fall in IOPTH values (PTH > 50% of baseline at 10 minutes) and yet the patient is cured, IOPTH monitoring would provide a false negative result. Neither of these scenarios conceptually is applicable to the situation of double parathyroid adenomas studied here. The terms false positive and true negative have special relevance to interpretation of IOPTH data in the setting of multiglandular disease. If IOPTH values fall below 50% of baseline by 10 minutes after excision of the first adenoma (a positive result thus suggesting cure), and there is 1 other abnormal
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parathyroid gland still in situ, but subsequently removed, this is considered a false positive result. If IOPTH values fail to fall below 50% of baseline by 10 minutes after excision of the first adenoma (a negative result suggesting failure to cure) and there indeed is 1 other abnormal parathyroid gland in situ, this is considered a true negative result. RESULTS All patients were biochemically cured of their hyperparathyroidism as determined by normal serum calcium at 1 day and again at 2 weeks to 3 weeks following operation. In addition, all patients remain eucalcemic with follow-up as long as 18 months, and none of the 20 patients have displayed evidence of persistent or recurrent hyperparathyroidism. All excised glands were hypercellular on final histology. See Table for a comparison of the study’s 2 subgroups. False positive results occurred in 11 of 20 patients (55%). The mean age of these patients was 65 years ± 3 years. The mean baseline PTH value was 142 pg/mL ± 25 pg/mL. The mean IOPTH values were 28% ± 4% at 5 minutes and 18% ± 2% at 10 minutes after excision of the first adenoma in these 11 patients (Figure). This kinetic pattern is strikingly similar to that seen with curative excision of a single parathyroid adenoma in the common scenario of single gland disease. Mean gland weights were 421 mg ± 102 mg for the first parathyroid gland and 162 mg ± 33 mg for the second parathyroid gland excised (Table). True negative results occurred in 9 of 20 patients (45%). The mean age of these patients was 65 years ± 4 years. The mean baseline PTH value was 213 pg/mL ± 47 pg/mL. The mean IOPTH values were 66% ± 7% at 5 minutes and 83% ± 15% at 10 minutes after excision of the first adenoma for these 9 patients (Figure). Mean gland weights were 801 mg ± 355 mg for the first parathyroid gland and 437 mg ± 141 mg for the second gland excised (Table). Using these figures, the specificity [true negative / (true negative + false positive)] of IOPTH in this defined setting was only 45%. DISCUSSION In this defined and relatively uncommon clinical scenario, IOPTH failed to detect consistently the presence of multiglandular disease, specifically double parathyroid adenomas. This finding contradicts one of the most important proposed uses for IOPTH monitoring. Other investigators have noted varying degrees of failure of IOPTH to detect multiglandular disease. Gordon et al1 studied the validity of IOPTH
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during conventional parathyroidectomy without using the data to guide their resection (bilateral exploration and resection based on gross morphologic assessment). IOPTH monitoring accurately predicted the disease state (uniglandular vs multiglandular disease) in 64 of the 72 patients (89%). In the patients with multiglandular disease, however, IOPTH had a false positive rate of 24%. That study is consistent with our experience in that all of these patients with false positive results had 2gland disease alone and that the second gland excised was smaller than the first as discussed below. Other groups have looked at the sensitivity of IOPTH in known multiglandular disease (not limited to double adenoma), such as the parathyroid lesion of multiple endocrine neoplasia type 1 (MEN 1). Even in MEN 1, a discrepancy between gland enlargement and gland hypersecretion may exist. In 16 patients with MEN 1 who underwent total parathyroidectomy and autotransplantation, 2 patients (12.5%) exhibited the kinetics of a single adenoma after removal of 1 large gland (a false positive test in terms of the residual multigland enlargement).2 We chose to limit our study group only to double adenomas and did not include patients with recognized multigland hyperplasia. After some initial debate in the pathology and surgery communities, it now generally is agreed that double parathyroid adenoma does exist as a separate clinical entity, but whether it can be distinguished clinically prior to operation is unknown.3,4 Tezelman et al5 analyzed patients with persistent or recurrent hyperparathyroidism based on either double adenoma or hyperplasia and found that recurrence rates after treatment were similarly low but the patients seemed clinically different. In specific, patients with double adenoma were older and had a higher incidence of symptoms such as muscle weakness, neuropsychiatric disorders, constipation, and weight loss. In contrast, Szabo et al6 found that their patients with double adenomas were clinically indistinguishable from patients with other histopathologic lesions. There essentially was no difference in age between the 2 groups analyzed in the present study (false positive 65 years ± 3 years vs true negative 65 years ± 4 years; P = .968) and we did not attempt to determine differences in symptomatology. Certain factors may have influenced our findings. As with any multicenter study, differences in surgical technique must be considered. Standard bilateral parathyroid exploration was performed similarly by both groups and determination of parathyroid gland abnormality was made on gross characteristics (mainly size > 70 mg estimated
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Figure. Intraoperative parathyroid hormone values after excision of first parathyroid adenoma.
mass). Neither group practices routine parathyroid biopsy to confirm normal parathyroid glands or to identify unsuspected hyperplastic parathyroid glands. The specific sequence of the complete exploration would have had no impact on the presence or recognition of the double parathyroid adenomas. The only conceivable influence of surgical technique on these results is the unlikely possibility that the second adenoma was devascularized during the process of its inspection. If this occurred before or during the excision of the first adenoma, the PTH decay kinetic curve of the second gland could be superimposed on the first and thus the residual PTH level would not be as high, therefore failing to indicate multiglandular disease. The fact that none of the 20 patients had prolonged temporary or permanent hypoparathyroidism and that both groups have permanent hypoparathyroidism rates of less than 2% is further argument against the influence of rough surgical technique. It is interesting to note that both the first and second adenoma removed generally were larger in the true negative group (801 mg ± 355 mg for the first parathyroid gland and 437 mg ± 141 mg for the second parathyroid gland excised) as compared to the false positive group (421 mg ± 102 mg for the first parathyroid and 162 mg ± 33 mg for the second parathyroid gland excised). This size discrepancy especially is relevant to the issue of the second adenoma. It is appealing conceptually to consider that the smaller gland may not be necessarily hypersecretory at the time of operation. Our figure of 162 mg ± 33 mg for the second gland is similar to the experience of Gordon et al,1 where patients with 2-gland parathyroid enlargement and failure to exhibit persistent biochemical evidence of hypersecretion had an average size of the second gland of 150 mg ± 60 mg.
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Table. Demographic and parathyroid specific characteristics of the study group False positive (FP) Age Male Female Baseline PTH 1st gland weight 2nd gland weight
65 ± 3 1 10 142 ± 25 421 ± 102 162 ± 33*
True negative (TN) 65 ± 4 5 4 213 ± 47 801 ± 355 437 ± 141†
FP vs TN P = .97 NS
P = .20 NS P = .33 NS P = .09 NS
NS, Not significant. *FP 1st gland vs FP 2nd gland; P = .03. †TN 1st gland vs TN 2nd gland; P = .36 NS.
One could argue that our patients actually had unrecognized multiglandular hyperplasia. During ongoing exploration, a mean of 1.6 ± 0.2 grossly normal parathyroid glands were seen. If failure to locate additional parathyroid glands translated to failure to recognize multiglandular hyperplasia, this effect would have the greatest implications for the false positive group in that additional abnormal glands would be present but not located definitively. It was actually in this group, however, that a relatively greater proportion of additional normal parathyroid glands were identified (mean of 1.7 ± 0.1 in the false positive group and 1.4 ± 0.3 in the true negative group; P = .40). The fact that all 20 patients have remained eucalcemic also mitigates against this, but longer follow-up would be required to state with certainty that unrecognized hyperplasia does not exist. Even if unrecognized hyperplasia existed in all 20 patients and all were therefore misclassified as double adenoma patients, it would not change the central message of this study. Double adenomas occurred in 4.4% of all patients undergoing parathyroidectomy during the study period. This is in keeping with the 1.9% to 12% incidence reported in other series.4,6-10 Molinari et al11 defined the incidence of multiglandular disease (2 or more glands) to be 5% when based on hypersecretion of PTH—not gross morphologic criteria. This is a lower percentage than reported based on gross morphologic criteria alone and again suggests that not all enlarged parathyroid glands are hypersecretory. It indeed is the inherent assumption that an enlarged gland is the same as a hypersecretory gland that is the most likely confounding factor for interpretation of our data. This is not a novel concept and this question has been raised by previous investigators.1,12 In the practice of conventional parathyroidectomy, an enlarged parathyroid gland may be removed on the basis of its gross characteristics only to find that final histology determines the gland normocellular. All parathyroid glands excised from these
patients during this study were originally and independently determined by pathologists to be hypercellular. Nevertheless, we cannot say for certain that all of these hypercellular glands were indeed hypersecretory. Perhaps our concepts of the histopathology and pathophysiology of primary hyperparathyroidism require reassessment. IOPTH monitoring clearly is the best test available to us to ascertain the functional significance of enlarged parathyroid glands at the time of surgery. Based on our current understanding of primary hyperparathyroidism, however, it still is an uncomfortable proposition to many parathyroid surgeons to leave a grossly enlarged parathyroid gland in situ based only on a curative fall in the IOPTH values after excision of the first gland alone. This is due to the concern of persistent or recurrent hyperparathyroidism based on this enlarged gland at some future time. If this approach were used, close long-term follow-up of the patients so treated would be required to answer the question of whether an enlarged gland is or later becomes hypersecretory. This unanswered question may have far-reaching implications as parathyroid surgery evolves toward minimally invasive parathyroidectomy without visualization of all parathyroid glands. At this time, the answer is incompletely known. Carneiro and Irvin12 have asserted that the fear of recurrence is unfounded based on a mean follow-up of 2.3 years for patients treated with a minimally invasive parathyroidectomy procedure. The authors state that an enlarged but unvisualized parathyroid gland will remain in 9% to 19% of cases that are treated with minimally invasive parathyroidectomy and admit that the follow-up period to date may be “premature to evaluate late recurrence.”12 While these findings may be generally encouraging, the study suffers from a noncurrent historical control group and the fact that patients with persistent hyperparathyroidism were excluded, thus obscuring the effect of any failure that was evident at an intermediate time period (after the postoperative period but before the
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6-month postoperative period by which recurrence is defined). For conventional parathyroidectomy, Proye et al13 point out that the surgical philosophy of excision of all grossly enlarged glands still is an acceptable and successful approach based on a mean follow-up of nearly 90 months in more than 300 patients with multiglandular disease. From a strictly pessimistic viewpoint, this negative study would suggest that double adenoma may be a potential cause for curative failure in approximately 4% of patients and that to apply minimally invasive parathyroidectomy and IOPTH to every patient could erode the success rate by approximately 2%. Overall, it has been a net gain in knowledge and sophistication in the aspects of imaging, hormonal measurement, and surgical technique that has pushed parathyroidectomy to evolve into a more targeted and slightly less invasive technique. IOPTH certainly does a great deal to ensure that the primary goal of a durable cure is preserved for the patient. IOPTH may not be perfect in every patient or clinical scenario, however, and we must continue to evaluate critically its optimal use. Longterm follow-up must continue to accrue to detect any early decrement in the long-term cure rate.
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CONCLUSIONS In patients undergoing conventional bilateral parathyroid exploration with removal of double parathyroid adenomas, IOPTH failed to reliably detect the presence of multiglandular disease, specifically double adenoma, using the criterion of a decrease in IOPTH values of less than 50% of baseline in the 10 minutes following excision of the first abnormal gland. These data should be considered when terminating a minimally invasive parathyroid exploration based on a curative fall in IOPTH values alone and point to the need for long-term follow-up in all patients so treated. Much remains to be learned about the true use of IOPTH in the presence of multiglandular disease. Although IOPTH will continue to be an increasingly valuable component of parathyroid surgery, it is important to consider that the data alone may not reflect perfectly the clinical scenario. IOPTH should enhance, but not supplant, the endocrine surgeon’s clinical judgment. REFERENCES 1. Gordon LL, Snyder WH, Wians F, Nwariaku F, Kim LT. The validity of quick intraoperative parathyroid hormone assay: an evaluation in 72 patients based on gross morphologic criteria. Surgery 1999;126:1030-5 2. Tonelli F, Spini S, Tommasi M, Gabbrielli G, Amorosi A, Brocchi A, et al. Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type I
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syndrome and hyperparathyroidism. World J Surg 2000;24:556-62. Harness JK, Ramsburg SR, Nishiyama RH, Thompson NW. Multiple adenomas of the parathyroids: do they exist? Arch Surg 1979;114:468-74. Verdonk CA, Edis AJ. Parathyroid “double adenomas”: fact or fiction? Surgery 1981;90:523-6. Tezelman S, Shen W, Siperstein AE, Duh QY, Clark OH. Persistent or recurrent hyperparathyroidism in patients with double adenomas. Surgery 1995;118:1115-24. Szabo E, Lundgren E, Juhlin C, Ljunghall S, Akerstrom G, Rastad J. Double parathyroid adenoma, a clinically nondistinct entity of primary hyperparathyroidism. World J Surg 1998;22:708-13. Attie JN, Bock G, Auguste LJ. Multiple parathyroid adenomas: report of 33 cases. Surgery 1990;108:1014-9. Bartsch D, Nies C, Hasse C, Willuhn J, Rothmund M. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995;82:926-9. Brothers TE, Thompson NW. Surgical treatment of primary hyperparathyroidism in elderly patients. Acta Chir Scand 1987;153:175-8. Uden P, Chan A, Duh QY, Siperstein A, Clark OH. Primary hyperparathyroidism in younger and older patients. Symptoms and outcome of surgery. World J Surg 1992; 16:791-7. Molinari AS, Irvin GL III, Deriso GT, Bott L. Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996;120:934-6. Carneiro DM, Irvin GL III. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925-9. Proye C, Carnaille B, Quievreux JL, Combemale F, Oudar C, Lecomte-Houcke M. Late outcome of 304 consecutive patients with multiple gland enlargement in primary hyperparathyroidism treated by conservative surgery. World J Surg 1998;22:526-9.
DISCUSSION Dr Collin Weber (Atlanta, Ga). As some of you may recall, I presented data quite similar to this 2 years ago, and our data continues to stand in compliance with yours. Paul Lo Gerfo explained the reason that I believe this occurs in the discussion of my paper. If you remember, there is an alteration of the setpoint for parathyroid hormone (PTH) release in abnormal parathyroid tumors. Ed Brown showed this to us in studies with Murray Brennan 25 years ago. What is the likelihood of a patient having 2 tumors with an identical set-point abnormality? I guess it can occur, but it probably is close to 0. So on the day that you or I operate on a patient with 2 tumors and we randomly take out the 1 that is the worst or the most dominant, the second one will not be functioning at that moment but it will tomorrow. Dr George Irvin (Miami, Fla). Let’s get our definitions straight. Intraoperative parathyroid hormone assay or IOPTH only does one thing. It measures the level of circulating hormone in the plasma. Because this hormone has a very short half-life, the assay is very accurate in predicting when all hypersecret-
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ing glands have been excised. It does not predict the size or the histopathology of parathyroid glands. This assay cannot predict what Dr Thompson’s group judged to be an enlarged gland, a second so-called adenoma. It does tell the surgeon, when the correct methodology is used, if excision of a suspected hypersecreting gland or glands will result in postoperative normocalcemia. This paper has similar results and the same flaw as the 2 papers presented before this group in 1999 by Dr Weber and by Dr Gordon and the group from Dallas. There is no evidence to show that the second adenoma was hyperfunctioning. My question really is then, how do you know that the second excised gland was secreting excess hormone when several investigators have shown that size and histopathology do not correlate with hormone secretion? Dr Gauger. Thank you for those comments, Dr Irvin. If you remember my conclusion, I agree with you in the sense that an enlarged gland does not necessarily equal a hypersecretory gland and vice versa. I am beginning to believe that there is a disconnection there, for some of the reasons that I talked about. The point you are making is, how does one know whether any of these patients who potentially will be left with missed enlarged glands are ever going to get into trouble? We don’t have that complete answer yet. This is why we all need ongoing long-term follow-up of these patients treated with minimally invasive procedures. As you point out, the issue about size and function certainly is not a new one. Dr Edwin Kaplan (Chicago, Ill). While IOPTH PTH has been very helpful in most cases, in 2 of 4 of our patients with double adenomas, the IOPTH PTH was misleading. In both cases, the PTH fell to less than 50% of the baseline value after removal of the larger gland. Fortunately, we continued to monitor the IOPTH PTH and with time the PTH rose again to the baseline value. A second enlarged gland was found and removed and the PTH fell dramatically thereafter. This situation is not dissimilar from what occurs with other endocrine tumors. If 2 insulinomas are present, for example, removal of one may result in a transient rise in glucose concentrations. Later, hypoglycemia occurs again until the remaining insulinoma is removed. Dr Barry Inabnet (New York, NY). I respectfully disagree with your conclusions. I think that your methodology is flawed in that you have excluded patients in your analysis who underwent a targeted parathyroidectomy with the added benefit of preoperative localization. I think that the IOPTH PTH assay does assist surgeons performing a targeted parathyroidectomy. This is a highly selected patient who has had a solitary adenoma visual-
Surgery December 2001 ized by preoperative imaging. In my experience of about 130 targeted parathyroid operations, the PTH assay correctly identified the 5% of patients with multiglandular disease. Dr Gauger. I appreciate your comments, but I am not sure they make any sense as far as the methodology is concerned. If you were to include those patients, I challenge you to tell me which of those patients that you are treating with a targeted exploration and single gland excision actually might have double adenomas and thus, which ones you would be worried about in the years to come. You don’t know that answer with any targeted procedure. This is the reason why we excluded those patients and included only patients who we could tell from the conventional procedure would fit into this narrowly defined patient subset. Dr Steven Libutti (Bethesda, Md). First of all, I want to congratulate you on a well-thought-out study and analysis. We also have been using the rapid intraoperative assay for several years now and looking at it in patients with known multigland disease, that is patients with MEN 1, as well as for the reoperative and first-time operations that we are conducting. One of the things we have witnessed, as you demonstrated in your study, is we have relied on the intraoperative assay in patients who ultimately had multigland disease, and yes, that second gland ultimately did function and result in the patient’s hypercalcemia. I want to point out one thing that might help make your results a little bit better than they were in terms of false positives and false negatives. Using the criteria of a drop in PTH by 50% at 10 minutes is a bit arbitrary and relies on an assumption of the half-life of PTH. We presented information to this forum in the past that the halflife varies from patient to patient to some degree, from 2 to 7 minutes in some cases, which can dramatically alter the decay curve. I would just like to suggest to all those who use the IOPTH PTH assay, which clearly has a role, to abandon a set 50% drop criteria at 10 minutes and use a kinetic analysis. This is a first order kinetic situation. As the glands are removed, the PTH will fall by first order kinetics, and by using a kinetic examination you really can predict where your ultimate baseline will wind up and not just use an arbitrary fall of 50%. Dr Gauger. I think you are right on target with that. I would just emphasize that the only clinically significant variance in the half-life may occur in those patients with a prolonged half-life. That would disproportionately impact the true negative group, not necessarily the false positive group. So I don’t think this factor, in and of itself, would have changed our findings.
Background. We hypothesized that intraoperative parathyroid hormone monitoring (IOPTH) reliably would detect double parathyroid adenomas. Methods. This was a retrospective study of 20 patients undergoing conventional parathyroidectomy with resection of exactly 2 abnormal glands. Full exploration was performed regardless of IOPTH values, which were measured after anesthetic induction and 5 and 10 minutes following removal of the first abnormal parathyroid gland. Failure to fall below 50% of baseline value by 10 minutes following resection of the first gland indicated the presence of multiglandular disease. Results. All patients were cured. All excised glands were hypercellular on histology. Mean IOPTH values in 9 of the 20 patients with true negative results (noncurative decrease, another gland present) were 66% ± 7% at 5 minutes and 83% ± 15% at 10 minutes. The IOPTH values in 11 of the 20 patients with false positive results (curative decrease, another gland present) were 28% ± 4% at 5 minutes and 18% ± 2% at 10 minutes. The false positive rate of IOPTH was 55%. Conclusions. We found that IOPTH failed to reliably detect the presence of double parathyroid adenomas. These data suggest that caution should be exercised when terminating limited parathyroid exploration based on a curative fall in IOPTH values. (Surgery 2001;130:1005-10.) From the University of Michigan Departments of Surgery and Pathology, Ann Arbor, Mich, and the Royal North Shore Hospital Departments of Surgery and Endocrinology, Sydney, New South Wales, Australia
INTRAOPERATIVE PARATHYROID HORMONE MONITORING (IOPTH) has been used to facilitate successful parathyroidectomy including minimally invasive techniques. Experience is rapidly accruing with this adjunctive technology and it is likely that it will remain an integral part of parathyroid surgery in the future. Endocrine surgeons still are learning the limits of the assay’s application to specific clinical situations, however. The technology may be changing the way in which we think about the pathophysiology of the different variants of hyperparathyroidism. The recognition of multiglandular disease is a facet of parathyroid surgery that Presented at the 22nd Annual Meeting of the American Association of Endocrine Surgeons, Atlanta, Ga, April 28-May 1, 2001. Reprint requests: Paul G. Gauger, MD, Assistant Professor of Surgery, University of Michigan Hospital, Department of Surgery—Division of Endocrine Surgery, 1500 E Medical Center Dr, TC 2920H, Ann Arbor, MI 48109-0331. Copyright © 2001 by Mosby, Inc. 0039-6060/2001/$35.00 + 0 11/6/118385 doi:10.1067/msy.2001.118385
continues as a problem with an imperfect solution. One proposed use of IOPTH is its ability to detect multiglandular disease allowing extension of the operation and ensuring cure of hyperparathyroidism, an issue especially relevant to minimally invasive parathyroidectomy techniques. Our hypothesis was that IOPTH consistently would predict the presence of multiglandular disease, specifically double parathyroid adenomas, which may be a cause of failed initial cervical exploration. The question asked with this study was whether excision of the first of 2 abnormal parathyroid glands consistently was associated with a noncurative fall in IOPTH values, suggesting the presence of the second abnormal parathyroid gland. METHODS This was a retrospective, multinational, 2-institution study of 20 patients treated from October 1999 through November 2000 at the University of Michigan Hospital in Ann Arbor, Mich, and the Royal North Shore Hospital in Sydney, Australia. During this defined time period, a combined total SURGERY 1005
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of 457 patients underwent parathyroidectomy at both institutions. The incidence of recognized double adenoma in these patients was 4.4%. All patients were treated as intended with a bilateral open parathyroid exploration, and the study group did not include patients undergoing minimally invasive parathyroidectomy because the existence of double adenoma could not otherwise be confirmed. Patients undergoing reoperation for persistent or recurrent hyperparathyroidism were not included. Each patient had exactly 2 abnormal parathyroid glands excised, and patients with recognized parathyroid hyperplasia were not included. The determination of an abnormal parathyroid gland was made on gross morphologic criteria, principally size greater than 70 mg estimated mass. During open parathyroidectomy, IOPTH values were measured at post-induction baseline and at 5 and 10 minutes following removal of the first abnormal parathyroid gland. Full parathyroid exploration was performed in all patients regardless of IOPTH values. In all cases, continued exploration revealed 1 other abnormal parathyroid gland that subsequently was removed. Biopsy of normal parathyroid glands was not performed routinely. Both institutions used the Immulite System (Diagnostic Products Corporation, Los Angeles, Calif). A fall of IOPTH values to less than or equal to 50% of baseline at 10 minutes following excision of the first gland was considered to indicate biochemical cure. Statistical analysis was performed using analysis of variance and independent t- tests, and the data below are expressed as mean ± standard error of the mean. What follows is an explanation of 4 terms as they apply in context to this study: 1) true positive, 2) false negative, 3) false positive, and 4) true negative. In the common situation in which only a single adenoma exists and is excised with a curative fall in IOPTH values (PTH ≤ 50% of baseline at 10 minutes after excision) and the patient is cured, this is a true positive result. In the situation in which a single adenoma exists and is excised with a noncurative fall in IOPTH values (PTH > 50% of baseline at 10 minutes) and yet the patient is cured, IOPTH monitoring would provide a false negative result. Neither of these scenarios conceptually is applicable to the situation of double parathyroid adenomas studied here. The terms false positive and true negative have special relevance to interpretation of IOPTH data in the setting of multiglandular disease. If IOPTH values fall below 50% of baseline by 10 minutes after excision of the first adenoma (a positive result thus suggesting cure), and there is 1 other abnormal
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parathyroid gland still in situ, but subsequently removed, this is considered a false positive result. If IOPTH values fail to fall below 50% of baseline by 10 minutes after excision of the first adenoma (a negative result suggesting failure to cure) and there indeed is 1 other abnormal parathyroid gland in situ, this is considered a true negative result. RESULTS All patients were biochemically cured of their hyperparathyroidism as determined by normal serum calcium at 1 day and again at 2 weeks to 3 weeks following operation. In addition, all patients remain eucalcemic with follow-up as long as 18 months, and none of the 20 patients have displayed evidence of persistent or recurrent hyperparathyroidism. All excised glands were hypercellular on final histology. See Table for a comparison of the study’s 2 subgroups. False positive results occurred in 11 of 20 patients (55%). The mean age of these patients was 65 years ± 3 years. The mean baseline PTH value was 142 pg/mL ± 25 pg/mL. The mean IOPTH values were 28% ± 4% at 5 minutes and 18% ± 2% at 10 minutes after excision of the first adenoma in these 11 patients (Figure). This kinetic pattern is strikingly similar to that seen with curative excision of a single parathyroid adenoma in the common scenario of single gland disease. Mean gland weights were 421 mg ± 102 mg for the first parathyroid gland and 162 mg ± 33 mg for the second parathyroid gland excised (Table). True negative results occurred in 9 of 20 patients (45%). The mean age of these patients was 65 years ± 4 years. The mean baseline PTH value was 213 pg/mL ± 47 pg/mL. The mean IOPTH values were 66% ± 7% at 5 minutes and 83% ± 15% at 10 minutes after excision of the first adenoma for these 9 patients (Figure). Mean gland weights were 801 mg ± 355 mg for the first parathyroid gland and 437 mg ± 141 mg for the second gland excised (Table). Using these figures, the specificity [true negative / (true negative + false positive)] of IOPTH in this defined setting was only 45%. DISCUSSION In this defined and relatively uncommon clinical scenario, IOPTH failed to detect consistently the presence of multiglandular disease, specifically double parathyroid adenomas. This finding contradicts one of the most important proposed uses for IOPTH monitoring. Other investigators have noted varying degrees of failure of IOPTH to detect multiglandular disease. Gordon et al1 studied the validity of IOPTH
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during conventional parathyroidectomy without using the data to guide their resection (bilateral exploration and resection based on gross morphologic assessment). IOPTH monitoring accurately predicted the disease state (uniglandular vs multiglandular disease) in 64 of the 72 patients (89%). In the patients with multiglandular disease, however, IOPTH had a false positive rate of 24%. That study is consistent with our experience in that all of these patients with false positive results had 2gland disease alone and that the second gland excised was smaller than the first as discussed below. Other groups have looked at the sensitivity of IOPTH in known multiglandular disease (not limited to double adenoma), such as the parathyroid lesion of multiple endocrine neoplasia type 1 (MEN 1). Even in MEN 1, a discrepancy between gland enlargement and gland hypersecretion may exist. In 16 patients with MEN 1 who underwent total parathyroidectomy and autotransplantation, 2 patients (12.5%) exhibited the kinetics of a single adenoma after removal of 1 large gland (a false positive test in terms of the residual multigland enlargement).2 We chose to limit our study group only to double adenomas and did not include patients with recognized multigland hyperplasia. After some initial debate in the pathology and surgery communities, it now generally is agreed that double parathyroid adenoma does exist as a separate clinical entity, but whether it can be distinguished clinically prior to operation is unknown.3,4 Tezelman et al5 analyzed patients with persistent or recurrent hyperparathyroidism based on either double adenoma or hyperplasia and found that recurrence rates after treatment were similarly low but the patients seemed clinically different. In specific, patients with double adenoma were older and had a higher incidence of symptoms such as muscle weakness, neuropsychiatric disorders, constipation, and weight loss. In contrast, Szabo et al6 found that their patients with double adenomas were clinically indistinguishable from patients with other histopathologic lesions. There essentially was no difference in age between the 2 groups analyzed in the present study (false positive 65 years ± 3 years vs true negative 65 years ± 4 years; P = .968) and we did not attempt to determine differences in symptomatology. Certain factors may have influenced our findings. As with any multicenter study, differences in surgical technique must be considered. Standard bilateral parathyroid exploration was performed similarly by both groups and determination of parathyroid gland abnormality was made on gross characteristics (mainly size > 70 mg estimated
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Figure. Intraoperative parathyroid hormone values after excision of first parathyroid adenoma.
mass). Neither group practices routine parathyroid biopsy to confirm normal parathyroid glands or to identify unsuspected hyperplastic parathyroid glands. The specific sequence of the complete exploration would have had no impact on the presence or recognition of the double parathyroid adenomas. The only conceivable influence of surgical technique on these results is the unlikely possibility that the second adenoma was devascularized during the process of its inspection. If this occurred before or during the excision of the first adenoma, the PTH decay kinetic curve of the second gland could be superimposed on the first and thus the residual PTH level would not be as high, therefore failing to indicate multiglandular disease. The fact that none of the 20 patients had prolonged temporary or permanent hypoparathyroidism and that both groups have permanent hypoparathyroidism rates of less than 2% is further argument against the influence of rough surgical technique. It is interesting to note that both the first and second adenoma removed generally were larger in the true negative group (801 mg ± 355 mg for the first parathyroid gland and 437 mg ± 141 mg for the second parathyroid gland excised) as compared to the false positive group (421 mg ± 102 mg for the first parathyroid and 162 mg ± 33 mg for the second parathyroid gland excised). This size discrepancy especially is relevant to the issue of the second adenoma. It is appealing conceptually to consider that the smaller gland may not be necessarily hypersecretory at the time of operation. Our figure of 162 mg ± 33 mg for the second gland is similar to the experience of Gordon et al,1 where patients with 2-gland parathyroid enlargement and failure to exhibit persistent biochemical evidence of hypersecretion had an average size of the second gland of 150 mg ± 60 mg.
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Table. Demographic and parathyroid specific characteristics of the study group False positive (FP) Age Male Female Baseline PTH 1st gland weight 2nd gland weight
65 ± 3 1 10 142 ± 25 421 ± 102 162 ± 33*
True negative (TN) 65 ± 4 5 4 213 ± 47 801 ± 355 437 ± 141†
FP vs TN P = .97 NS
P = .20 NS P = .33 NS P = .09 NS
NS, Not significant. *FP 1st gland vs FP 2nd gland; P = .03. †TN 1st gland vs TN 2nd gland; P = .36 NS.
One could argue that our patients actually had unrecognized multiglandular hyperplasia. During ongoing exploration, a mean of 1.6 ± 0.2 grossly normal parathyroid glands were seen. If failure to locate additional parathyroid glands translated to failure to recognize multiglandular hyperplasia, this effect would have the greatest implications for the false positive group in that additional abnormal glands would be present but not located definitively. It was actually in this group, however, that a relatively greater proportion of additional normal parathyroid glands were identified (mean of 1.7 ± 0.1 in the false positive group and 1.4 ± 0.3 in the true negative group; P = .40). The fact that all 20 patients have remained eucalcemic also mitigates against this, but longer follow-up would be required to state with certainty that unrecognized hyperplasia does not exist. Even if unrecognized hyperplasia existed in all 20 patients and all were therefore misclassified as double adenoma patients, it would not change the central message of this study. Double adenomas occurred in 4.4% of all patients undergoing parathyroidectomy during the study period. This is in keeping with the 1.9% to 12% incidence reported in other series.4,6-10 Molinari et al11 defined the incidence of multiglandular disease (2 or more glands) to be 5% when based on hypersecretion of PTH—not gross morphologic criteria. This is a lower percentage than reported based on gross morphologic criteria alone and again suggests that not all enlarged parathyroid glands are hypersecretory. It indeed is the inherent assumption that an enlarged gland is the same as a hypersecretory gland that is the most likely confounding factor for interpretation of our data. This is not a novel concept and this question has been raised by previous investigators.1,12 In the practice of conventional parathyroidectomy, an enlarged parathyroid gland may be removed on the basis of its gross characteristics only to find that final histology determines the gland normocellular. All parathyroid glands excised from these
patients during this study were originally and independently determined by pathologists to be hypercellular. Nevertheless, we cannot say for certain that all of these hypercellular glands were indeed hypersecretory. Perhaps our concepts of the histopathology and pathophysiology of primary hyperparathyroidism require reassessment. IOPTH monitoring clearly is the best test available to us to ascertain the functional significance of enlarged parathyroid glands at the time of surgery. Based on our current understanding of primary hyperparathyroidism, however, it still is an uncomfortable proposition to many parathyroid surgeons to leave a grossly enlarged parathyroid gland in situ based only on a curative fall in the IOPTH values after excision of the first gland alone. This is due to the concern of persistent or recurrent hyperparathyroidism based on this enlarged gland at some future time. If this approach were used, close long-term follow-up of the patients so treated would be required to answer the question of whether an enlarged gland is or later becomes hypersecretory. This unanswered question may have far-reaching implications as parathyroid surgery evolves toward minimally invasive parathyroidectomy without visualization of all parathyroid glands. At this time, the answer is incompletely known. Carneiro and Irvin12 have asserted that the fear of recurrence is unfounded based on a mean follow-up of 2.3 years for patients treated with a minimally invasive parathyroidectomy procedure. The authors state that an enlarged but unvisualized parathyroid gland will remain in 9% to 19% of cases that are treated with minimally invasive parathyroidectomy and admit that the follow-up period to date may be “premature to evaluate late recurrence.”12 While these findings may be generally encouraging, the study suffers from a noncurrent historical control group and the fact that patients with persistent hyperparathyroidism were excluded, thus obscuring the effect of any failure that was evident at an intermediate time period (after the postoperative period but before the
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6-month postoperative period by which recurrence is defined). For conventional parathyroidectomy, Proye et al13 point out that the surgical philosophy of excision of all grossly enlarged glands still is an acceptable and successful approach based on a mean follow-up of nearly 90 months in more than 300 patients with multiglandular disease. From a strictly pessimistic viewpoint, this negative study would suggest that double adenoma may be a potential cause for curative failure in approximately 4% of patients and that to apply minimally invasive parathyroidectomy and IOPTH to every patient could erode the success rate by approximately 2%. Overall, it has been a net gain in knowledge and sophistication in the aspects of imaging, hormonal measurement, and surgical technique that has pushed parathyroidectomy to evolve into a more targeted and slightly less invasive technique. IOPTH certainly does a great deal to ensure that the primary goal of a durable cure is preserved for the patient. IOPTH may not be perfect in every patient or clinical scenario, however, and we must continue to evaluate critically its optimal use. Longterm follow-up must continue to accrue to detect any early decrement in the long-term cure rate.
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CONCLUSIONS In patients undergoing conventional bilateral parathyroid exploration with removal of double parathyroid adenomas, IOPTH failed to reliably detect the presence of multiglandular disease, specifically double adenoma, using the criterion of a decrease in IOPTH values of less than 50% of baseline in the 10 minutes following excision of the first abnormal gland. These data should be considered when terminating a minimally invasive parathyroid exploration based on a curative fall in IOPTH values alone and point to the need for long-term follow-up in all patients so treated. Much remains to be learned about the true use of IOPTH in the presence of multiglandular disease. Although IOPTH will continue to be an increasingly valuable component of parathyroid surgery, it is important to consider that the data alone may not reflect perfectly the clinical scenario. IOPTH should enhance, but not supplant, the endocrine surgeon’s clinical judgment. REFERENCES 1. Gordon LL, Snyder WH, Wians F, Nwariaku F, Kim LT. The validity of quick intraoperative parathyroid hormone assay: an evaluation in 72 patients based on gross morphologic criteria. Surgery 1999;126:1030-5 2. Tonelli F, Spini S, Tommasi M, Gabbrielli G, Amorosi A, Brocchi A, et al. Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type I
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syndrome and hyperparathyroidism. World J Surg 2000;24:556-62. Harness JK, Ramsburg SR, Nishiyama RH, Thompson NW. Multiple adenomas of the parathyroids: do they exist? Arch Surg 1979;114:468-74. Verdonk CA, Edis AJ. Parathyroid “double adenomas”: fact or fiction? Surgery 1981;90:523-6. Tezelman S, Shen W, Siperstein AE, Duh QY, Clark OH. Persistent or recurrent hyperparathyroidism in patients with double adenomas. Surgery 1995;118:1115-24. Szabo E, Lundgren E, Juhlin C, Ljunghall S, Akerstrom G, Rastad J. Double parathyroid adenoma, a clinically nondistinct entity of primary hyperparathyroidism. World J Surg 1998;22:708-13. Attie JN, Bock G, Auguste LJ. Multiple parathyroid adenomas: report of 33 cases. Surgery 1990;108:1014-9. Bartsch D, Nies C, Hasse C, Willuhn J, Rothmund M. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995;82:926-9. Brothers TE, Thompson NW. Surgical treatment of primary hyperparathyroidism in elderly patients. Acta Chir Scand 1987;153:175-8. Uden P, Chan A, Duh QY, Siperstein A, Clark OH. Primary hyperparathyroidism in younger and older patients. Symptoms and outcome of surgery. World J Surg 1992; 16:791-7. Molinari AS, Irvin GL III, Deriso GT, Bott L. Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996;120:934-6. Carneiro DM, Irvin GL III. Late parathyroid function after successful parathyroidectomy guided by intraoperative hormone assay (QPTH) compared with the standard bilateral neck exploration. Surgery 2000;128:925-9. Proye C, Carnaille B, Quievreux JL, Combemale F, Oudar C, Lecomte-Houcke M. Late outcome of 304 consecutive patients with multiple gland enlargement in primary hyperparathyroidism treated by conservative surgery. World J Surg 1998;22:526-9.
DISCUSSION Dr Collin Weber (Atlanta, Ga). As some of you may recall, I presented data quite similar to this 2 years ago, and our data continues to stand in compliance with yours. Paul Lo Gerfo explained the reason that I believe this occurs in the discussion of my paper. If you remember, there is an alteration of the setpoint for parathyroid hormone (PTH) release in abnormal parathyroid tumors. Ed Brown showed this to us in studies with Murray Brennan 25 years ago. What is the likelihood of a patient having 2 tumors with an identical set-point abnormality? I guess it can occur, but it probably is close to 0. So on the day that you or I operate on a patient with 2 tumors and we randomly take out the 1 that is the worst or the most dominant, the second one will not be functioning at that moment but it will tomorrow. Dr George Irvin (Miami, Fla). Let’s get our definitions straight. Intraoperative parathyroid hormone assay or IOPTH only does one thing. It measures the level of circulating hormone in the plasma. Because this hormone has a very short half-life, the assay is very accurate in predicting when all hypersecret-
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ing glands have been excised. It does not predict the size or the histopathology of parathyroid glands. This assay cannot predict what Dr Thompson’s group judged to be an enlarged gland, a second so-called adenoma. It does tell the surgeon, when the correct methodology is used, if excision of a suspected hypersecreting gland or glands will result in postoperative normocalcemia. This paper has similar results and the same flaw as the 2 papers presented before this group in 1999 by Dr Weber and by Dr Gordon and the group from Dallas. There is no evidence to show that the second adenoma was hyperfunctioning. My question really is then, how do you know that the second excised gland was secreting excess hormone when several investigators have shown that size and histopathology do not correlate with hormone secretion? Dr Gauger. Thank you for those comments, Dr Irvin. If you remember my conclusion, I agree with you in the sense that an enlarged gland does not necessarily equal a hypersecretory gland and vice versa. I am beginning to believe that there is a disconnection there, for some of the reasons that I talked about. The point you are making is, how does one know whether any of these patients who potentially will be left with missed enlarged glands are ever going to get into trouble? We don’t have that complete answer yet. This is why we all need ongoing long-term follow-up of these patients treated with minimally invasive procedures. As you point out, the issue about size and function certainly is not a new one. Dr Edwin Kaplan (Chicago, Ill). While IOPTH PTH has been very helpful in most cases, in 2 of 4 of our patients with double adenomas, the IOPTH PTH was misleading. In both cases, the PTH fell to less than 50% of the baseline value after removal of the larger gland. Fortunately, we continued to monitor the IOPTH PTH and with time the PTH rose again to the baseline value. A second enlarged gland was found and removed and the PTH fell dramatically thereafter. This situation is not dissimilar from what occurs with other endocrine tumors. If 2 insulinomas are present, for example, removal of one may result in a transient rise in glucose concentrations. Later, hypoglycemia occurs again until the remaining insulinoma is removed. Dr Barry Inabnet (New York, NY). I respectfully disagree with your conclusions. I think that your methodology is flawed in that you have excluded patients in your analysis who underwent a targeted parathyroidectomy with the added benefit of preoperative localization. I think that the IOPTH PTH assay does assist surgeons performing a targeted parathyroidectomy. This is a highly selected patient who has had a solitary adenoma visual-
Surgery December 2001 ized by preoperative imaging. In my experience of about 130 targeted parathyroid operations, the PTH assay correctly identified the 5% of patients with multiglandular disease. Dr Gauger. I appreciate your comments, but I am not sure they make any sense as far as the methodology is concerned. If you were to include those patients, I challenge you to tell me which of those patients that you are treating with a targeted exploration and single gland excision actually might have double adenomas and thus, which ones you would be worried about in the years to come. You don’t know that answer with any targeted procedure. This is the reason why we excluded those patients and included only patients who we could tell from the conventional procedure would fit into this narrowly defined patient subset. Dr Steven Libutti (Bethesda, Md). First of all, I want to congratulate you on a well-thought-out study and analysis. We also have been using the rapid intraoperative assay for several years now and looking at it in patients with known multigland disease, that is patients with MEN 1, as well as for the reoperative and first-time operations that we are conducting. One of the things we have witnessed, as you demonstrated in your study, is we have relied on the intraoperative assay in patients who ultimately had multigland disease, and yes, that second gland ultimately did function and result in the patient’s hypercalcemia. I want to point out one thing that might help make your results a little bit better than they were in terms of false positives and false negatives. Using the criteria of a drop in PTH by 50% at 10 minutes is a bit arbitrary and relies on an assumption of the half-life of PTH. We presented information to this forum in the past that the halflife varies from patient to patient to some degree, from 2 to 7 minutes in some cases, which can dramatically alter the decay curve. I would just like to suggest to all those who use the IOPTH PTH assay, which clearly has a role, to abandon a set 50% drop criteria at 10 minutes and use a kinetic analysis. This is a first order kinetic situation. As the glands are removed, the PTH will fall by first order kinetics, and by using a kinetic examination you really can predict where your ultimate baseline will wind up and not just use an arbitrary fall of 50%. Dr Gauger. I think you are right on target with that. I would just emphasize that the only clinically significant variance in the half-life may occur in those patients with a prolonged half-life. That would disproportionately impact the true negative group, not necessarily the false positive group. So I don’t think this factor, in and of itself, would have changed our findings.