Ann Surg Oncol (2014) 21:1369–1373 DOI 10.1245/s10434-013-3402-y
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Parathyroid Surgery in the Elderly: Should Minimally Invasive Surgery Be Abandoned? Michal Mekel, MD1,2, Hayim Gilshtein, MD1, Katya Chapchay, MD3, Bishara Bishara, MD1,2, Michael M. Krausz, MD2,4, Herbert R. Freund, MD3, Yoram Kluger, MD1,2, Ahmed Eid, MD3, and Haggi Mazeh, MD3 Department of General Surgery, Rambam-Health Care Campus, Haifa, Israel; 2Technion—Israel Institute of Technology, Haifa, Israel; 3Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4Hillel Yaffe Medical Center, Hadera, Israel 1
ABSTRACT Background. Single adenoma is the cause of 80 % of primary hyperparathyroidism (PHPT) resulting in wide acceptance of minimally invasive parathyroidectomy (MIP). The incidence of PHPT increases with age. Little information is available regarding the prevalence of multiglandular disease (MGD) in older patients. Methods. The records of 537 patients that underwent parathyroid surgery between January 2005 and October 2012 at two endocrine surgery referral centers were retrospectively reviewed. Comparison was performed between patients younger than 65 and older than 65 years of age. Clinical variables included preoperative laboratories and imaging, extent of neck exploration, number of glands excised, and intraoperative parathyroid hormone levels during surgery. Results. There were 374 (70 %) patients in the younger age group (YG) and 163 (30 %) patients in the older age group (OG). The mean age was 50 ± 0.5 and 71 ± 0.4 years, respectively. There was no difference between the groups in terms of gender or laboratory results. MGD was significantly more common in the OG (24 % vs. 12 %; p = 0.001) and similarly MIP was less commonly completed in the OG (49 % vs. 68 %; p \ 0.001). Cure rates were comparable between the OG and YG (93 % vs. 95 %; p = 0.27). In the OG, patients with MGD had significantly smaller glands as compared to patients with single adenomas in this group (331 ± 67 vs. 920 ± 97 mg; p = 0.006, respectively).
Ó Society of Surgical Oncology 2013 First Received: 26 April 2013; Published Online: 4 December 2013 M. Mekel, MD e-mail: [email protected]
Conclusions. MGD in PHPT was found to be more prevalent in older patients. Planning a bilateral neck exploration should be considered in older patients, especially when a relatively small gland is suggested by imaging or encountered during surgery. Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder. Recent epidemiologic studies in the United States and Europe have found incidences between 36.3 and 146.0 per 100,000 person-years for women and between 13.4 and 79.5 per 100,000 personyears in men.1,2 PHPT predominantly affects older patients with peak incidences between the ages of 55 and 74.3 In general, single adenomas (SA) account for PHPT in more than 80 % of cases and more than one abnormal parathyroid gland is present in about 15–20 %.4–7 In these cases, multigland hyperplasia is usually the cause, reported in 12– 20 %, whereas double adenomas (DA) have been reported in 2–7 % of patients. Although several studies have investigated the role of gender and ethnicity in multiglandular disease (MGD) in PHPT, only few addressed the issue of MGD in older patients. Some have shown no difference in parathyroid pathology between older and younger patients,8–10 whereas others indicate increased rates of DA and hyperplasia the older.11,12 The fact that most cases of PHPT are caused by an SA and the improvement in preoperative localization studies have led to the wide acceptance of minimally invasive parathyroidectomy (MIP) as the procedure of choice for selected patients with positive preoperative imaging studies. Intraoperative parathyroid hormone (IoPTH) plays a pivotal role in MIP and different protocols define cure criteria.13,14 In cases of normal-appearing parathyroid gland or when IoPTH levels do not meet the criteria for a cure, MIP is converted to either unilateral neck exploration
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(UNE) or bilateral neck exploration (BNE). Conversion to BNE after inadequate IoPTH drop may be time consuming (depending on institutional equipment), as intraoperative decision-making awaits the laboratory results. Therefore, it is important to identify a subgroup of patients at increased risk for MGD that may consequently benefit from upfront BNE. We hypothesized that the development of MGD may be gradual and asymmetric and therefore the risk of finding MGD in older patients may be higher. The aim of this study was to determine the rate of MGD in older patients, and to identify patients in whom BNE should be planned in advance or decided upon early during surgery.
more than one enlarged gland that was confirmed then on histology. Surgical cure was defined as a decrease in postexcision IoPTH level by more than 50 % from its preincision value. Recurrent disease was diagnosed when patients had an initial successful operation, maintained normal serum PTH and calcium levels for at least 6 months, and only then developed recurrent disease. Subgroup analysis was performed for the OG and compared patients with MGD to those with an SA, including the same pre-operative, intraoperative, and outcome characteristics.
PATIENTS AND METHODS
T test and Chi square analysis were applied to identify differences between the older and younger groups, as well as for the univariate analysis of the subgroups. Statistical calculations were completed using statistical software (SPSS version 21; SPSS, Inc., Chicago, IL, USA) and a p value \ 0.05 was considered to represent statistical significance for all comparisons.
The study was approved by the Institutional Review Board. Between January 2005 and October 2012, 537 consecutive patients underwent parathyroid surgery for PHPT at two endocrine surgery referral centers (Rambam Medical Center and Hadassah-Hebrew University Medical Center). Their records were retrospectively reviewed and a comparison was made between patients younger than 65, referred to as the younger group (YG), and patients at the age of 65 years and older, referred to as the older group (OG). Clinical variables included preoperative laboratories, imaging studies, extent of neck exploration, number of glands excised, and IoPTH levels. Most patients underwent both Technetium-99m Sestamibi (MIBI) scan and neck ultrasound (US) before surgery. The US was routinely performed by a radiologist. In recent years a surgeon-performed US gained acceptance and was also performed at the clinic and/or operating room. The surgical approach began with MIP when both MIBI and US localized an SA or when one study localized an adenoma and the other did not. UNE was defined as the exploration of two parathyroid glands on one side, and when both sides of the neck were explored it was considered a BNE. A pre-incision IoPTH level was drawn in all patients at the beginning of surgery and at 10 min (and in most patients also at 20 min) from the excision of the enlarged parathyroid gland(s). Intact parathyroid hormone (PTH) STAT assay (Roche Diagnostics GmbH, Mannheim, Germany) was used in all cases. Conversion to UNE or BNE was performed when findings during surgery did not match imaging findings (i.e., when the index gland was not found in the presumed location, or when the IoPTH level did not adequately drop). The BNE was preplanned in cases in which imaging studies were discordant or when none of them localized an adenoma. MGD was defined when inappropriate decrease in IoPTH prompted further dissection with identification of other enlarged glands or when intraoperative findings included
Statistical Analysis
RESULTS There were 537 consecutive patients that were retrospectively reviewed. The mean preoperative calcium and PTH levels were 11.2 ± 0.1 mg/dL and 192 ± 14 pg/ml (normal 10–72), respectively. The US and MIBI scans were performed in 98 and 97 % of patients of the entire cohort, respectively. Of the entire cohort, MIP was attempted in 87 % of the patients, and of those, it was successfully completed in 71 %. Only 13 % had a preplanned BNE. The mean length of follow-up for the entire cohort was 57 ± 1.2 months (range 12–96 months). The overall cure rate was 94 % and recurrence was documented in 1.3 % of patients. There was only one case of recurrent laryngeal nerve injury and four cases of permanent hypoparathyroidism. There were no cases of neck hematoma. There were 374 (70 %) patients in the YG and 163 (30 %) patients in the OG. There was no difference between the two groups in terms of gender, preoperative calcium level, and PTH level (Table 1). The rate of MGD was significantly higher in the OG compared with the YG (24 % vs. 12 %, respectively; p = 0.001). Interestingly, the rate of suggested MGD by preoperative imaging was comparable between the OG and YG (12 % vs. 8 %, respectively; p = 0.24). As illustrated in Fig. 1, MIP was less often completed in the OG compared with the YG (49 % vs. 68 %; p \ 0.001, respectively). The mean final level of IoPTH was significantly lower in the YG compared with the OG (40 ng/L vs. 51 ng/L, respectively; p = 0.003). Cure rates were comparable between the OG
Parathyroid Surgery in the Elderly
1371 Patients (%)
TABLE 1 Demographic and pre-operative characteristics Variable
Younger group (N = 374)
Older group (N = 163)
p value
Female:male
3.3:1
3.3:1
0.56
Age (years), mean (range) 49.9 (13–64)
71.1 (65–87)
–
Calcium, mean ± SEM (mg/dl) PTH, mean ± SEM (ng/L)
11.18 ± 0.05
11.19 ± 0.08
0.99
174 ± 7
231 ± 42
0.37
30
Creatinine [ 1.5 mg/dL, n (%)
1 (0.3)
4 (2.5)
0.21
20
History of lithium use, n (%) History of head/neck irradiation, n (%)
3 (0.8)
2 (1.2)
0.55
10
2 (0.5)
2 (1.2)
0.59
SEM standard error of mean, PTH parathyroid hormone
and YG (93 % and 95 %, respectively; p = 0.28). Mean length of follow-up was not significantly different between the OG and YG (54 ± 2.1 vs. 58 ± 1.4 months, respectively; p = 0.17). The recurrence rate was similar between the two groups (1.4 and 1.2 % in the YG and OG, respectively; p = not significant). Within the OG, there were no significant differences between patients with an SA to those with MGD in terms of age, gender, and preoperative laboratory results (Table 2). The US and MIBI scans accurately localized the diseased glands in 77 and 80 % of patients with an SA (p \ 0.001). Although preoperative PTH levels were not significantly different between the subgroups, highest IoPTH levels were significantly higher in the MGD group with no difference in the final IoPTH. Mean gland weight was smaller in patients with MGD as compared to patients with SA (Table 3). DISCUSSION Traditionally, the debate hinged on whether or not surgical treatment should be offered to older patients due to unpredictable risk of surgery in light of their comorbidities. Since then, studies have shown parathyroid surgery in older patients to be safe with equal outcomes compared to the younger patients.8,15–18 Consensus guidelines have set the threshold for treating all patients with PHPT under the age of 50, whereas patients over the age of 50 are referred for surgery only in cases of symptomatic disease or with disease specific complications.19 However, patients with elevated PTH resulting from primary or secondary hyperparathyroidism have been shown to be at higher risk not only for disease-specific complication, but also for cardiovascular morbidity and mortality20,21; this has urged endocrinologists to refer older patients with comorbidities
P < 0.001
70
YG
60
OG
50 40
MIP
MIP converted to UNE
MIP converted to BNE
Planned BNE
FIG. 1 Surgical procedure performed by age group. MIP minimally invasive parathyroidectomy, UNE unilateral neck exploration, BNE bilateral neck exploration
TABLE 2 Older group analysis, demographic and preoperative characteristics Variable
Single adenoma (N = 124; 76 %)
Female:male
3:01
MGD (N = 39; 24 %)
p value
4.5:1
0.37
Age (years), mean (range) 71
72
0.22
Preoperative calcium, 11.22 ± 0.1 mean ± SEM (mg/dL)
11.09 ± 0.15 0.5
Preoperative PTH, mean ± SEM (ng/L)
326 ± 154
201 ± 24
0.2
MGD multiglandular disease, SEM standard error of mean, PTH parathyroid hormone
to surgery more liberally. As the population ages, more older patients are expected to present with PHPT. In our series, 30 % of patients operated on during the study period were over the age of 65 years. This corresponds to similar rates of older patients operated on for PHPT in epidemiologic and clinical studies.22,23 Therefore, research should focus on characterizing the pathophysiology of the disease in older patients in an effort to optimize surgical care. Our study is one of the few addressing this issue. Since the advent of localization studies in the early 1990s, the traditional four gland exploration was replaced by MIP, allowing minimal dissection, shorter operative time, and surgery under ambulatory settings.24 A few studies questioned the use of IoPTH as a determinant of surgical success, claiming that it can underestimate the presence of additional parathyroid tumors. Siperstein et al.4 found that among patients who underwent a simulated focal exploration with concordant US and MIBI scan, and
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TABLE 3 Older group analysis, intraoperative biochemistry and outcome Variable
Single adenoma (N = 124)
MGD (N = 39)
p value
Highest IoPTH, mean ± SEM 194 ± 14 (ng/L)
385 ± 160 0.04
Final IoPTH, mean ± SEM (ng/L)
48 ± 3
57 ± 8
0.25
Largest parathyroid gland weight, mean ± SEM (mg)
920 ± 97
331 ± 67
0.009
Cure rate (%)
93
90
0.76
IoPTH intraoperative parathyroid hormone, SEM standard error of mean
whose IoPTH dropped appropriately after resecting the index gland, occult MGD was discovered in 16 % at BNE. In a recent publication, an article by Norman et al.25 further suggested that the only way to achieve a cure rate of nearly 100 % is to evaluate all four parathyroid glands. In their study, Norman et al.25 demonstrated that cure rates for patients undergoing UNE were significantly lower than cure rates in patients undergoing BNE. Possible higher long-term recurrence rates associated with MIP were also suggested by Schneider et al.26 in a large cohort of patients. Nevertheless, routine BNE may result in increased operative complications; therefore, we believe that the MIP with its various protocols should be adopted, while identifying subsets of patients that may benefit from a pre-planned BNE. Older patients may constitute such a group.27 The purpose of this study was to evaluate the rate of MGD in older patients. We found that MGD was significantly more common in older patients compared to younger patients, with rates of 24 % MGD in older patients. In a study by Politz and Norman,9 octogenarians were compared to younger patients and no difference was found between the incidence of SA, DA, or hyperplasia when MIP was the common procedure. It is interesting, however, that results were different when the common procedure used was BNE, before the advent of IoPTH. Uden et al.11 showed that DA was significantly more common in patients older than 60 compared with younger patients (9.2 % vs. 2.5 %, respectively).In a study by Kebebew et al.12 26 % of octogenarians had MGD. These results are similar to those presented in this current study. The conversion rate for our group of older patients was 32 %. This was usually a result of inappropriate decrease in IoPTH levels. The IoPTH assay in our institution takes 30 min, including the 10–20 min wait until the IoPTH measurement is obtained. The average wait time for the result is 45 min. Nehs et al.28 found that four gland exploration had a significantly decreased operative time compared
with UNE and ascribed this finding to the processing time for the PTH assay. Furthermore, they found a 50 % false-negative rate for the IoPTH assay when conversion to BNE was guided by the IoPTH result, but contralateral disease was present in only 50 % of these patients. Awaiting results of IoPTH prolongs anesthesia, which may pose an increased risk in this particular population. The mean final IoPTH was 51 pg/mL for our OG patients, significantly higher compared with the YG. Heller and Blumberg29 found that patients with a final IoPTH level of 40 pg/mL or higher are at higher risk of having persistent hyperparathyroidism and should be followed up closely and indefinitely after parathyroidectomy. Data in the literature is lacking regarding the kinetics of PTH in older patients. Another possible explanation for differences in final IoPTH may be the use of bisphosphonates that is more common in the OG. Finally, older patients with MGD in our study were found to have significantly higher levels of the highest IoPTH with significantly lower gland weight. The recently published Wisconsin Index nomogram predicts the likelihood of an additional hyperfunctioning gland.30 The current findings correlate with the notion suggested by the Wisconsin Index that high PTH (and calcium) levels in the face of an encountered small gland suggest an additional hyperfunctioning gland. We acknowledge the fact that our study may have a referral bias as we encounter more older patients without localization that were deferred surgery by other surgeons considering their age, comorbidities, and lack of localization. The rate of MGD may still be underestimated in older patients because endocrinologists hesitate to send patients without localization to surgery, specifically if older in age with comorbidities. Another limitation of the study is the lack of vitamin D levels, which were not available for most patients. The retrospective study design poses another bias, and the authors intend to perform a randomized prospective study evaluating the efficacy of BNE in older patients. In conclusion, our findings suggest that older patients commonly have MGD. Comparable cure rates with younger patients confirm surgery as the best treatment option in older patients as well. Selection pre-operatively, or an early decision during surgery, to convert to BNE may shorten operating time. Pre-operatively, higher rates of conversion to BNE should be discussed with the patient, and method of anesthesia (local, regional, or general) should be appropriately considered. A more challenging disease accompanied with higher morbidity in older patients should prompt referral to high volume centers. Once operated on, an intraoperative decision may be based on highest IoPTH levels and index gland weight. Prospective studies are required to understand the pathophysiology of the disease in the aged and determine the true rate of MGD in this population.
Parathyroid Surgery in the Elderly DISCLOSURES
The authors have made no disclosures.
REFERENCES 1. Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 2013;98:1122–9. 2. Yu N, Donnan PT, Murphy MJ, Leese GP. Epidemiology of primary hyperparathyroidism in Tayside, Scotland, UK. Clin Endocrinol (Oxf). 2009;71:485–93. 3. Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease. J Bone Miner Res. 2006;21:171–7. 4. Siperstein A, Berber E, Barbosa GF, et al. Predicting the success of limited exploration for primary hyperparathyroidism using ultrasound, sestamibi, and intraoperative parathyroid hormone: analysis of 1158 cases. Ann Surg. 2008;248:420–8. 5. Kebebew E, Hwang J, Reiff E, Duh QY, Clark OH. Predictors of single-gland vs multigland parathyroid disease in primary hyperparathyroidism: a simple and accurate scoring model. Arch Surg. 2006;141:777–82; discussion 782. 6. Grant CS, Thompson G, Farley D, van Heerden J. Primary hyperparathyroidism surgical management since the introduction of minimally invasive parathyroidectomy: Mayo Clinic experience. Arch Surg. May 2005;140(5):472–8; discussion 478–9. 7. Thompson NW, Eckhauser FE, Harness JK. The anatomy of primary hyperparathyroidism. Surgery. 1982;92:814–21. 8. Chen H, Parkerson S, Udelsman R. Parathyroidectomy in the elderly: do the benefits outweigh the risks? World J Surg. 1998;22:531–5; discussion 535–6. 9. Politz D, Norman J. Hyperparathyroidism in patients over 80: clinical characteristics and their ability to undergo outpatient parathyroidectomy. Thyroid. 2007;17:333–9. 10. Stechman MJ, Weisters M, Gleeson FV, Sadler GP, Mihai R. Parathyroidectomy is safe and improves symptoms in elderly patients with primary hyperparathyroidism (PHPT). Clin Endocrinol (Oxf). 2009;71:787–91. 11. 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; discussion 798. 12. Kebebew E, Duh QY, Clark OH. Parathyroidectomy for primary hyperparathyroidism in octogenarians and nonagenarians: a plea for early surgical referral. Arch Surg.2003;138:867–71. 13. Richards ML, Thompson GB, Farley DR, Grant CS. An optimal algorithm for intraoperative parathyroid hormone monitoring. Arch Surg. 2011;146(3):280–5. 14. Starker LF, Fonseca AL, Carling T, Udelsman R. Minimally invasive parathyroidectomy. Int J Endocrinol. 2011;2011: 206502.
1373 15. Egan KR, Adler JT, Olson JE, Chen H. Parathyroidectomy for primary hyperparathyroidism in octogenarians and nonagenarians: a risk-benefit analysis. J Surg Res. 2007;140:194–8. 16. Morris LF, Zelada J, Wu B, Hahn TJ, Yeh MW. Parathyroid surgery in the elderly. Oncologist. 2010;15:1273–84. 17. Shin SH, Holmes H, Bao R, et al. Outpatient minimally invasive parathyroidectomy is safe for elderly patients. J Am Coll Surg. 2009;208:1071–6. 18. Bachar G, Gilat H, Mizrachi A, et al. Comparison of perioperative management and outcome of parathyroidectomy between older and younger patients. Head Neck. 2008;30:1415–21. 19. Bilezikian JP, Khan AA, Potts JT, Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94:335–9. 20. Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease–a review. Eur Heart J. 2004;25:1776–87. 21. Hagstrom E, Hellman P, Larsson TE, et al. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119:2765–71. 22. Miller BS, Dimick J, Wainess R, Burney RE. Age- and sexrelated incidence of surgically treated primary hyperparathyroidism. World J Surg. 2008;32:795–9. 23. Young VN, Osborne KM, Fleming MM, Flynn MB, Goldstein RE, Bumpous JM. Parathyroidectomy in the elderly population: does age really matter? Laryngoscope. 2010;120(2):247–52. 24. Irvin GL, 3rd, Carneiro DM, Solorzano CC. Progress in the operative management of sporadic primary hyperparathyroidism over 34 years. Ann Surg. 2004;239:704–8; discussion 708–11. 25. 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(3):260–9. 26. Schneider DF, Mazeh H, Sippel RS, et al. Is minimally invasive parathyroidectomy associated with greater recurrence compared to bilateral exploration? Analysis of more than 1,000 cases. Surgery. 2012;152:1008–15. 27. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial. Ann Surg. 2002;236:543–51. 28. Nehs MA, Ruan DT, Gawande AA, Moore FD, Jr., Cho NL. Bilateral neck exploration decreases operative time compared to minimally invasive parathyroidectomy in patients with discordant imaging. World J Surg. 2013;37:1614–7. 29. Heller KS, Blumberg SN. Relation of final intraoperative parathyroid hormone level and outcome following parathyroidectomy. Arch Otolaryngol Head Neck Surg. 2009;135:1103–7. 30. Mazeh H, Chen H, Leverson G, Sippel RS. Creation of a ‘‘Wisconsin index’’ nomogram to predict the likelihood of additional hyperfunctioning parathyroid glands during parathyroidectomy. Ann Surg. 2013;257:138–41.
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Parathyroid Surgery in the Elderly: Should Minimally Invasive Surgery Be Abandoned? Michal Mekel, MD1,2, Hayim Gilshtein, MD1, Katya Chapchay, MD3, Bishara Bishara, MD1,2, Michael M. Krausz, MD2,4, Herbert R. Freund, MD3, Yoram Kluger, MD1,2, Ahmed Eid, MD3, and Haggi Mazeh, MD3 Department of General Surgery, Rambam-Health Care Campus, Haifa, Israel; 2Technion—Israel Institute of Technology, Haifa, Israel; 3Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4Hillel Yaffe Medical Center, Hadera, Israel 1
ABSTRACT Background. Single adenoma is the cause of 80 % of primary hyperparathyroidism (PHPT) resulting in wide acceptance of minimally invasive parathyroidectomy (MIP). The incidence of PHPT increases with age. Little information is available regarding the prevalence of multiglandular disease (MGD) in older patients. Methods. The records of 537 patients that underwent parathyroid surgery between January 2005 and October 2012 at two endocrine surgery referral centers were retrospectively reviewed. Comparison was performed between patients younger than 65 and older than 65 years of age. Clinical variables included preoperative laboratories and imaging, extent of neck exploration, number of glands excised, and intraoperative parathyroid hormone levels during surgery. Results. There were 374 (70 %) patients in the younger age group (YG) and 163 (30 %) patients in the older age group (OG). The mean age was 50 ± 0.5 and 71 ± 0.4 years, respectively. There was no difference between the groups in terms of gender or laboratory results. MGD was significantly more common in the OG (24 % vs. 12 %; p = 0.001) and similarly MIP was less commonly completed in the OG (49 % vs. 68 %; p \ 0.001). Cure rates were comparable between the OG and YG (93 % vs. 95 %; p = 0.27). In the OG, patients with MGD had significantly smaller glands as compared to patients with single adenomas in this group (331 ± 67 vs. 920 ± 97 mg; p = 0.006, respectively).
Ó Society of Surgical Oncology 2013 First Received: 26 April 2013; Published Online: 4 December 2013 M. Mekel, MD e-mail: [email protected]
Conclusions. MGD in PHPT was found to be more prevalent in older patients. Planning a bilateral neck exploration should be considered in older patients, especially when a relatively small gland is suggested by imaging or encountered during surgery. Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder. Recent epidemiologic studies in the United States and Europe have found incidences between 36.3 and 146.0 per 100,000 person-years for women and between 13.4 and 79.5 per 100,000 personyears in men.1,2 PHPT predominantly affects older patients with peak incidences between the ages of 55 and 74.3 In general, single adenomas (SA) account for PHPT in more than 80 % of cases and more than one abnormal parathyroid gland is present in about 15–20 %.4–7 In these cases, multigland hyperplasia is usually the cause, reported in 12– 20 %, whereas double adenomas (DA) have been reported in 2–7 % of patients. Although several studies have investigated the role of gender and ethnicity in multiglandular disease (MGD) in PHPT, only few addressed the issue of MGD in older patients. Some have shown no difference in parathyroid pathology between older and younger patients,8–10 whereas others indicate increased rates of DA and hyperplasia the older.11,12 The fact that most cases of PHPT are caused by an SA and the improvement in preoperative localization studies have led to the wide acceptance of minimally invasive parathyroidectomy (MIP) as the procedure of choice for selected patients with positive preoperative imaging studies. Intraoperative parathyroid hormone (IoPTH) plays a pivotal role in MIP and different protocols define cure criteria.13,14 In cases of normal-appearing parathyroid gland or when IoPTH levels do not meet the criteria for a cure, MIP is converted to either unilateral neck exploration
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(UNE) or bilateral neck exploration (BNE). Conversion to BNE after inadequate IoPTH drop may be time consuming (depending on institutional equipment), as intraoperative decision-making awaits the laboratory results. Therefore, it is important to identify a subgroup of patients at increased risk for MGD that may consequently benefit from upfront BNE. We hypothesized that the development of MGD may be gradual and asymmetric and therefore the risk of finding MGD in older patients may be higher. The aim of this study was to determine the rate of MGD in older patients, and to identify patients in whom BNE should be planned in advance or decided upon early during surgery.
more than one enlarged gland that was confirmed then on histology. Surgical cure was defined as a decrease in postexcision IoPTH level by more than 50 % from its preincision value. Recurrent disease was diagnosed when patients had an initial successful operation, maintained normal serum PTH and calcium levels for at least 6 months, and only then developed recurrent disease. Subgroup analysis was performed for the OG and compared patients with MGD to those with an SA, including the same pre-operative, intraoperative, and outcome characteristics.
PATIENTS AND METHODS
T test and Chi square analysis were applied to identify differences between the older and younger groups, as well as for the univariate analysis of the subgroups. Statistical calculations were completed using statistical software (SPSS version 21; SPSS, Inc., Chicago, IL, USA) and a p value \ 0.05 was considered to represent statistical significance for all comparisons.
The study was approved by the Institutional Review Board. Between January 2005 and October 2012, 537 consecutive patients underwent parathyroid surgery for PHPT at two endocrine surgery referral centers (Rambam Medical Center and Hadassah-Hebrew University Medical Center). Their records were retrospectively reviewed and a comparison was made between patients younger than 65, referred to as the younger group (YG), and patients at the age of 65 years and older, referred to as the older group (OG). Clinical variables included preoperative laboratories, imaging studies, extent of neck exploration, number of glands excised, and IoPTH levels. Most patients underwent both Technetium-99m Sestamibi (MIBI) scan and neck ultrasound (US) before surgery. The US was routinely performed by a radiologist. In recent years a surgeon-performed US gained acceptance and was also performed at the clinic and/or operating room. The surgical approach began with MIP when both MIBI and US localized an SA or when one study localized an adenoma and the other did not. UNE was defined as the exploration of two parathyroid glands on one side, and when both sides of the neck were explored it was considered a BNE. A pre-incision IoPTH level was drawn in all patients at the beginning of surgery and at 10 min (and in most patients also at 20 min) from the excision of the enlarged parathyroid gland(s). Intact parathyroid hormone (PTH) STAT assay (Roche Diagnostics GmbH, Mannheim, Germany) was used in all cases. Conversion to UNE or BNE was performed when findings during surgery did not match imaging findings (i.e., when the index gland was not found in the presumed location, or when the IoPTH level did not adequately drop). The BNE was preplanned in cases in which imaging studies were discordant or when none of them localized an adenoma. MGD was defined when inappropriate decrease in IoPTH prompted further dissection with identification of other enlarged glands or when intraoperative findings included
Statistical Analysis
RESULTS There were 537 consecutive patients that were retrospectively reviewed. The mean preoperative calcium and PTH levels were 11.2 ± 0.1 mg/dL and 192 ± 14 pg/ml (normal 10–72), respectively. The US and MIBI scans were performed in 98 and 97 % of patients of the entire cohort, respectively. Of the entire cohort, MIP was attempted in 87 % of the patients, and of those, it was successfully completed in 71 %. Only 13 % had a preplanned BNE. The mean length of follow-up for the entire cohort was 57 ± 1.2 months (range 12–96 months). The overall cure rate was 94 % and recurrence was documented in 1.3 % of patients. There was only one case of recurrent laryngeal nerve injury and four cases of permanent hypoparathyroidism. There were no cases of neck hematoma. There were 374 (70 %) patients in the YG and 163 (30 %) patients in the OG. There was no difference between the two groups in terms of gender, preoperative calcium level, and PTH level (Table 1). The rate of MGD was significantly higher in the OG compared with the YG (24 % vs. 12 %, respectively; p = 0.001). Interestingly, the rate of suggested MGD by preoperative imaging was comparable between the OG and YG (12 % vs. 8 %, respectively; p = 0.24). As illustrated in Fig. 1, MIP was less often completed in the OG compared with the YG (49 % vs. 68 %; p \ 0.001, respectively). The mean final level of IoPTH was significantly lower in the YG compared with the OG (40 ng/L vs. 51 ng/L, respectively; p = 0.003). Cure rates were comparable between the OG
Parathyroid Surgery in the Elderly
1371 Patients (%)
TABLE 1 Demographic and pre-operative characteristics Variable
Younger group (N = 374)
Older group (N = 163)
p value
Female:male
3.3:1
3.3:1
0.56
Age (years), mean (range) 49.9 (13–64)
71.1 (65–87)
–
Calcium, mean ± SEM (mg/dl) PTH, mean ± SEM (ng/L)
11.18 ± 0.05
11.19 ± 0.08
0.99
174 ± 7
231 ± 42
0.37
30
Creatinine [ 1.5 mg/dL, n (%)
1 (0.3)
4 (2.5)
0.21
20
History of lithium use, n (%) History of head/neck irradiation, n (%)
3 (0.8)
2 (1.2)
0.55
10
2 (0.5)
2 (1.2)
0.59
SEM standard error of mean, PTH parathyroid hormone
and YG (93 % and 95 %, respectively; p = 0.28). Mean length of follow-up was not significantly different between the OG and YG (54 ± 2.1 vs. 58 ± 1.4 months, respectively; p = 0.17). The recurrence rate was similar between the two groups (1.4 and 1.2 % in the YG and OG, respectively; p = not significant). Within the OG, there were no significant differences between patients with an SA to those with MGD in terms of age, gender, and preoperative laboratory results (Table 2). The US and MIBI scans accurately localized the diseased glands in 77 and 80 % of patients with an SA (p \ 0.001). Although preoperative PTH levels were not significantly different between the subgroups, highest IoPTH levels were significantly higher in the MGD group with no difference in the final IoPTH. Mean gland weight was smaller in patients with MGD as compared to patients with SA (Table 3). DISCUSSION Traditionally, the debate hinged on whether or not surgical treatment should be offered to older patients due to unpredictable risk of surgery in light of their comorbidities. Since then, studies have shown parathyroid surgery in older patients to be safe with equal outcomes compared to the younger patients.8,15–18 Consensus guidelines have set the threshold for treating all patients with PHPT under the age of 50, whereas patients over the age of 50 are referred for surgery only in cases of symptomatic disease or with disease specific complications.19 However, patients with elevated PTH resulting from primary or secondary hyperparathyroidism have been shown to be at higher risk not only for disease-specific complication, but also for cardiovascular morbidity and mortality20,21; this has urged endocrinologists to refer older patients with comorbidities
P < 0.001
70
YG
60
OG
50 40
MIP
MIP converted to UNE
MIP converted to BNE
Planned BNE
FIG. 1 Surgical procedure performed by age group. MIP minimally invasive parathyroidectomy, UNE unilateral neck exploration, BNE bilateral neck exploration
TABLE 2 Older group analysis, demographic and preoperative characteristics Variable
Single adenoma (N = 124; 76 %)
Female:male
3:01
MGD (N = 39; 24 %)
p value
4.5:1
0.37
Age (years), mean (range) 71
72
0.22
Preoperative calcium, 11.22 ± 0.1 mean ± SEM (mg/dL)
11.09 ± 0.15 0.5
Preoperative PTH, mean ± SEM (ng/L)
326 ± 154
201 ± 24
0.2
MGD multiglandular disease, SEM standard error of mean, PTH parathyroid hormone
to surgery more liberally. As the population ages, more older patients are expected to present with PHPT. In our series, 30 % of patients operated on during the study period were over the age of 65 years. This corresponds to similar rates of older patients operated on for PHPT in epidemiologic and clinical studies.22,23 Therefore, research should focus on characterizing the pathophysiology of the disease in older patients in an effort to optimize surgical care. Our study is one of the few addressing this issue. Since the advent of localization studies in the early 1990s, the traditional four gland exploration was replaced by MIP, allowing minimal dissection, shorter operative time, and surgery under ambulatory settings.24 A few studies questioned the use of IoPTH as a determinant of surgical success, claiming that it can underestimate the presence of additional parathyroid tumors. Siperstein et al.4 found that among patients who underwent a simulated focal exploration with concordant US and MIBI scan, and
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M. Mekel et al.
TABLE 3 Older group analysis, intraoperative biochemistry and outcome Variable
Single adenoma (N = 124)
MGD (N = 39)
p value
Highest IoPTH, mean ± SEM 194 ± 14 (ng/L)
385 ± 160 0.04
Final IoPTH, mean ± SEM (ng/L)
48 ± 3
57 ± 8
0.25
Largest parathyroid gland weight, mean ± SEM (mg)
920 ± 97
331 ± 67
0.009
Cure rate (%)
93
90
0.76
IoPTH intraoperative parathyroid hormone, SEM standard error of mean
whose IoPTH dropped appropriately after resecting the index gland, occult MGD was discovered in 16 % at BNE. In a recent publication, an article by Norman et al.25 further suggested that the only way to achieve a cure rate of nearly 100 % is to evaluate all four parathyroid glands. In their study, Norman et al.25 demonstrated that cure rates for patients undergoing UNE were significantly lower than cure rates in patients undergoing BNE. Possible higher long-term recurrence rates associated with MIP were also suggested by Schneider et al.26 in a large cohort of patients. Nevertheless, routine BNE may result in increased operative complications; therefore, we believe that the MIP with its various protocols should be adopted, while identifying subsets of patients that may benefit from a pre-planned BNE. Older patients may constitute such a group.27 The purpose of this study was to evaluate the rate of MGD in older patients. We found that MGD was significantly more common in older patients compared to younger patients, with rates of 24 % MGD in older patients. In a study by Politz and Norman,9 octogenarians were compared to younger patients and no difference was found between the incidence of SA, DA, or hyperplasia when MIP was the common procedure. It is interesting, however, that results were different when the common procedure used was BNE, before the advent of IoPTH. Uden et al.11 showed that DA was significantly more common in patients older than 60 compared with younger patients (9.2 % vs. 2.5 %, respectively).In a study by Kebebew et al.12 26 % of octogenarians had MGD. These results are similar to those presented in this current study. The conversion rate for our group of older patients was 32 %. This was usually a result of inappropriate decrease in IoPTH levels. The IoPTH assay in our institution takes 30 min, including the 10–20 min wait until the IoPTH measurement is obtained. The average wait time for the result is 45 min. Nehs et al.28 found that four gland exploration had a significantly decreased operative time compared
with UNE and ascribed this finding to the processing time for the PTH assay. Furthermore, they found a 50 % false-negative rate for the IoPTH assay when conversion to BNE was guided by the IoPTH result, but contralateral disease was present in only 50 % of these patients. Awaiting results of IoPTH prolongs anesthesia, which may pose an increased risk in this particular population. The mean final IoPTH was 51 pg/mL for our OG patients, significantly higher compared with the YG. Heller and Blumberg29 found that patients with a final IoPTH level of 40 pg/mL or higher are at higher risk of having persistent hyperparathyroidism and should be followed up closely and indefinitely after parathyroidectomy. Data in the literature is lacking regarding the kinetics of PTH in older patients. Another possible explanation for differences in final IoPTH may be the use of bisphosphonates that is more common in the OG. Finally, older patients with MGD in our study were found to have significantly higher levels of the highest IoPTH with significantly lower gland weight. The recently published Wisconsin Index nomogram predicts the likelihood of an additional hyperfunctioning gland.30 The current findings correlate with the notion suggested by the Wisconsin Index that high PTH (and calcium) levels in the face of an encountered small gland suggest an additional hyperfunctioning gland. We acknowledge the fact that our study may have a referral bias as we encounter more older patients without localization that were deferred surgery by other surgeons considering their age, comorbidities, and lack of localization. The rate of MGD may still be underestimated in older patients because endocrinologists hesitate to send patients without localization to surgery, specifically if older in age with comorbidities. Another limitation of the study is the lack of vitamin D levels, which were not available for most patients. The retrospective study design poses another bias, and the authors intend to perform a randomized prospective study evaluating the efficacy of BNE in older patients. In conclusion, our findings suggest that older patients commonly have MGD. Comparable cure rates with younger patients confirm surgery as the best treatment option in older patients as well. Selection pre-operatively, or an early decision during surgery, to convert to BNE may shorten operating time. Pre-operatively, higher rates of conversion to BNE should be discussed with the patient, and method of anesthesia (local, regional, or general) should be appropriately considered. A more challenging disease accompanied with higher morbidity in older patients should prompt referral to high volume centers. Once operated on, an intraoperative decision may be based on highest IoPTH levels and index gland weight. Prospective studies are required to understand the pathophysiology of the disease in the aged and determine the true rate of MGD in this population.
Parathyroid Surgery in the Elderly DISCLOSURES
The authors have made no disclosures.
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