Paradigm Shift in the Surgical Management of Multigland Parathyroid Hyperplasia: An Individualized Approach

Importance  Locoregional anesthesia, conscious sedation, and exploration via a limited incision have become a well-accepted approach for the treatment of patients with primary hyperparathyroidism with image-localized, presumed single-gland disease. However, to our knowledge, this minimally invasive technique has never been investigated in patients with multigland disease.

Objective  To extrapolate the technique of locoregional anesthesia, conscious sedation, and exploration via a limited incision to perform minimally invasive bilateral exploration in patients who have multigland hyperplasia.

Design, Setting, and Participants  Retrospective analysis at a tertiary academic referral center of 100 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism due to parathyroid hyperplasia between January 19, 2010, and July 30, 2013, who were included in a prospective database.

Interventions  All patients underwent subtotal parathyroidectomy using either conventional treatment (bilateral neck exploration under general anesthesia) or extended minimally invasive parathyroidectomy (ex-MIP; locoregional anesthesia, conscious sedation, and exploration via a limited incision). Patients in the ex-MIP group who required conversion to general anesthesia were analyzed in the ex-MIP group on an intent-to-treat basis.

Main Outcomes and Measures  Patient cure and complication rates, length of stay, and total hospital charges.

Results  Of the 100 consecutive patients with parathyroid hyperplasia, 29 received conventional treatment and 71 underwent ex-MIP. In the ex-MIP group, 11 of 71 patients (15.5%) required conversion to general anesthesia. There were no differences between the ex-MIP and conventional treatment groups in age (mean [SD], 62.2 [12.2] vs 57.7 [15.2] years; P = .12), sex (59 [83.1%] vs 23 [79.3%] female; P = .78), preoperative serum calcium level (mean [SD], 11.1 [0.9] vs 10.8 [0.8] mg/dL; to convert to millimoles per liter, multiply by 0.25; P = .15), preoperative serum parathyroid hormone level (mean [SD], 114.5 [56.8] vs 137.8 [83.4] pg/mL; to convert to nanograms per liter, multiply by 1; P = .10), complications (4 vs 0 complications; P = .32), or cure rates (98.6% vs 96.6%; P = .50). Importantly, the ex-MIP group had a significant reduction in length of stay compared with the conventional treatment group (mean [SD], 1.01 [0.02] vs 1.35 [0.24] days; P = .04). They also had lower total hospital charges, but the difference was not statistically significant (mean, $23 199 vs $27 312; P = .17).

Conclusions and Relevance  Parathyroidectomy with bilateral neck exploration under general anesthesia has been the standard of care for the treatment of parathyroid hyperplasia. We demonstrate that ex-MIP can provide equivalent cure and complication rates with a shorter hospital stay and a mean hospital charge reduction of more than $4000 per case.

Although primary hyperparathyroidism (PHPT) is a common endocrine disorder with approximately 100 000 new cases diagnosed per year in the United States, multigland disease represents only 10% to 15% of cases.^1-3 Regardless of etiology, parathyroidectomy is the sole curative treatment option for PHPT; it improves symptoms and bone density, enhances quality of life, and resolves metabolic complications.⁴

Traditional parathyroid surgery encompassed bilateral cervical exploration to identify all parathyroid glands and resect the enlarged, hyperfunctioning gland(s). Improvements in preoperative localization modalities with a corresponding surge toward less invasive interventions led to the development of focused, limited, minimally invasive parathyroidectomy (MIP) explorations. We have shown that MIP is more effective than classic bilateral cervical exploration and is associated with reduced complication rates and costs.^3,5,6 The definition of MIP continues to be debated.⁷ Some define MIP based on its unilateral, image-guided approach. Others emphasize the use of locoregional anesthesia, conscious sedation, and exploration via a limited incision. To avoid these competing definitions, we propose a new term, extended MIP (ex-MIP), for a minimally invasive technique through a small incision using locoregional anesthesia, conscious sedation, and bilateral exploration.^8-10 This ex-MIP approach expands the operative field, permitting visualization of all parathyroid glands, and expands use of minimally invasive techniques that have traditionally been restricted to unilateral, image-guided parathyroidectomies in single-gland disease to patients with multigland disease. The surgeon can tailor the extent of the exploration based on intraoperative findings, independent of preoperative imaging results.

The utility of this individualized ex-MIP approach was investigated by a proof-of-concept study to compare the results of ex-MIP with conventional parathyroid surgery for hyperplasia-induced PHPT.

The records of 100 consecutive parathyroid explorations for PHPT due to multigland hyperplasia were reviewed by analyzing a prospective database. All patients underwent parathyroidectomy by a single surgeon at a tertiary care academic medical center between January 19, 2010, and July 30, 2013. The database and this study were approved by the Yale Human Investigation Committee. The requirement for written informed consent was waived as the research presented no more than minimal risk of harm to participants and involved no procedures for which written informed consent is normally required.

Standardized and prospective data were obtained preoperatively, perioperatively, and postoperatively. The database comprised demographic characteristics, symptoms and signs, biochemical data, imaging, operative, and pathological findings, and follow-up information. In all cases, the biochemical diagnosis was confirmed by measurements of serum intact parathyroid hormone (PTH) and calcium levels. Pathological confirmation and follow-up laboratory data were obtained for all patients to confirm multigland hyperplasia and test for biochemical cure, respectively.

The surgeon performed either a subtotal parathyroidectomy, using conventional bilateral neck exploration under general anesthesia, or ex-MIP, consisting of locoregional anesthesia, surgeon-administered bilateral anterior cervical block analgesia, conscious sedation, and exploration via a limited incision. Refinements in our technique allowed extension of the MIP approach, expanding the operative field to visualize all parathyroid glands in an awake patient. Because the etiology is often uncertain before the exploration, the ex-MIP approach allowed for individual variation depending on the operative findings and allowed the surgeon to confirm the functional integrity of the recurrent laryngeal nerves by asking the patient to phonate during the exploration. When a case was extended from a unilateral to bilateral approach, the surgeon always assessed the patient’s voice to be certain that the side of the initial exploration had a functioning recurrent laryngeal nerve.

Patient demographic characteristics, cure and complication rates, length of stay (LOS), and total hospital charges are summarized. Patient characteristics are reported as the mean (standard deviation) for continuous variables and as a proportion for categorical variables. Differences at baseline comparing patient characteristics between the ex-MIP and conventional treatment groups were assessed using the t test (normal distribution) or Mann-Whitney U test (nonnormal distribution) for continuous variables and the χ² or Fisher exact test, where appropriate, for categorical variables. Cost data were derived from total hospital charges, including the charge for the operative procedure, intraoperative PTH analyses, and all hospital costs associated with admission. They did not include the costs of clinic visits or preoperative imaging studies in either group. GraphPad Prism software version 6.0c (GraphPad Software, Inc) was used to perform statistical analysis and plot data. All significance tests were 2-sided and the α level was set at .05. Patients in the ex-MIP group who required conversion to general anesthesia were analyzed in the ex-MIP group on an intent-to-treat basis.

Between January 1, 2010, and July 31, 2013, 401 patients were evaluated for PHPT and underwent parathyroidectomy. Of these, 100 underwent parathyroidectomy for multigland hyperplasia. Of the 100 patients, 29 received conventional treatment and 71 underwent ex-MIP (Table 1).

Remedial cervical exploration was performed in 3 patients in the conventional treatment group and 3 in the ex-MIP group owing to persistent or recurrent PHPT; all of these patients had initial exploration elsewhere. The 29 patients in the conventional treatment group were excluded from ex-MIP for the following reasons: physician preference in anticipation of a complicated parathyroid exploration (n = 10), need for concomitant thyroidectomy (n = 6), syndromic disease (multiple endocrine neoplasia type 1; n = 6), a large multinodular goiter (n = 2), patient’s desire (n = 2), requirement for simultaneous cervical thymectomy (n = 1), underlying neurological disorder (dystonia; n = 1), and hypercalcemic crisis (n = 1) (Table 2).

All patients had preoperative biochemical confirmation of PHPT demonstrated by an elevated serum calcium level (>10.5 mg/dL; to convert to millimoles per liter, multiply by 0.25) in conjunction with an elevated or inappropriate intact serum PTH level (>65 pg/mL; to convert to nanograms per liter, multiply by 1) in the setting of normal renal function.

The majority of patients were women (82.0%). The mean (SEM) age was 61 (13) years, and age ranged from 19 to 86 years.

There were no differences between the ex-MIP and conventional treatment groups in age (mean [SD], 62.2 [12.2] vs 57.7 [15.2] years; P = .12), sex (59 [83.1%] vs 23 [79.3%]; P = .78), preoperative serum calcium level (mean [SD], 11.1 [0.9] vs 10.8 [0.8] mg/dL; P = .15), or preoperative serum PTH level (mean [SD], 114.5 [56.8] vs 137.8 [83.4] pg/mL; P = .10). The elevated preoperative serum calcium and PTH levels resolved postoperatively (calcium: mean [SD], 9.11 [0.72] vs 8.99 [0.71] mg/dL; P = .41; PTH: mean [SD], 16.72 [18.51] vs 11.80 [14.94] pg/mL; P = .21). The signs and symptoms at presentation are shown in Table 1. There were no significant differences comparing the demographic characteristics, signs, and symptoms between the 2 groups (P > .05).

In the ex-MIP group, 11 of 71 patients (15.5%) required conversion to general anesthesia (Table 2). Conversions were owing to case complexity (n = 9), concomitant thyroidectomy (n = 1), or a static postresection PTH level (n = 1).

There were 4 complications in the ex-MIP group, including 1 recurrent nerve injury and 3 pneumothoraces. The complications were because of ectopic and/or mediastinal explorations. There were no complications in the conventional treatment group. However, the difference in complication rates comparing the 2 groups was not statistically significant (P = .32).

The cure rate was indistinguishable between the ex-MIP and conventional treatment groups (98.6% vs 96.6%; P = .50). In analyzing the biochemical results, 2 patients were found not to be cured, including 1 in the ex-MIP group and 1 remedial exploration that was started as ex-MIP but was converted to general anesthesia owing to a static PTH level. The overall cure rate was 98.0%.

The mean (SD) hospital LOS of 1.01 (0.02) days for the patients who underwent ex-MIP compared favorably with the mean (SD) LOS of 1.35 (0.24) days for patients who underwent conventional parathyroid exploration (P = .04). The mean LOS for all of these patients is higher than that of our patients with a single adenoma.⁶ This is reflective of our policy to admit patients for subtotal resection owing to their inherent risk of developing postoperative hypocalcemia. These findings remained unchanged when the data were stratified by new and remedial explorations.

This favorable effect of ex-MIP on LOS had a financial impact on total hospital charges. When comparing the mean cost of ex-MIP with that of conventional parathyroid explorations ($23 199 vs $27 312; P = .17), the mean savings per individual patient undergoing ex-MIP was $4113. The mean total hospital charge in remedial ex-MIP was also lower when compared with conventional parathyroid explorations ($19 441 vs $28 354), but the difference was not statistically significant (P = .07).

This study is the first, to our knowledge, to investigate the role of a MIP exploration for patients with PHPT due to multigland disease, which is traditionally managed by bilateral cervical neck exploration under general anesthesia. We propose the term ex-MIP, denoting 4-gland parathyroid exploration through a limited surgical excision using locoregional anesthesia and conscious sedation. Our data indicate that ex-MIP has similar outcomes in select patients with multigland hyperplasia, providing an equal rate of cure and complications with the advantage of decreased LOS and total hospital charges. Although traditionally suited for patients with a single-gland parathyroid adenoma, our results encourage the adoption of minimally invasive techniques in the surgical management of PHPT due to multigland disease.

The introduction of serum calcium measurements in the late 1970s led to an increase in diagnoses of asymptomatic PHPT, and multiple expert panels subsequently indicated that patients with asymptomatic PHPT frequently benefit from surgery.³ Knowing that a single parathyroid adenoma is the most common cause of PHPT, these patients are offered extirpation of the culprit parathyroid gland, leaving the nondiseased glands in situ.

Advancements in the field of parathyroid surgery led to the introduction of a focused, minimally invasive approach, which has been proven to be an attractive option to obtain excellent cure rates and minimize complications and costs. The resurgence of locoregional anesthesia techniques by Lo Gerfo¹¹ further revolutionized parathyroid surgery, offering treatment in awake patients and extending the patient population. Specifically, locoregional anesthesia was deemed acceptable for patients who were not previously surgical candidates owing to general anesthesia risks. We refined this technique by using intraoperative PTH assays and combining the focused, image-directed approach with locoregional anesthesia techniques.^5,6,10 However, these minimally invasive techniques were exclusively considered in patients with single-gland disease in which preoperative localization studies identified a single adenoma. It is of paramount importance to distinguish patients with 4-gland parathyroid hyperplasia from those with parathyroid adenomas as they are treated differently. Multigland hyperplasia is treated with subtotal parathyroidectomy requiring visualization of all parathyroid glands and subsequent resection of 3½ glands, a procedure that has been exclusively performed by bilateral cervical neck exploration under general anesthesia.

Encouraged by our success with minimally invasive techniques in PHPT due to single-gland disease, we extrapolated our minimally invasive technique to the more complex population of patients with bilateral multigland parathyroid hyperplasia. The study results show that ex-MIP is a safe procedure that offers advantages when compared with traditional parathyroid surgery.

Despite these encouraging findings, several limitations of our study are noted. The absence of randomization between the 2 techniques makes the study subject to inherent bias. The surgeon who performed all operations preferentially used ex-MIP unless precluded by patient preference or other contraindications, such as a concomitant thyroid disease or coexisting multiple endocrine neoplasia disorders. This liberal approach of offering most patients ex-MIP explains the 15% conversion rate to general anesthesia and conventional surgery. We do not have complete outpatient cost data inclusive of imaging studies in either group. Although we have complete short-term follow-up data for every patient, we lack long-term follow-up data from all patients. The data confirm short-term cure, but long-term results will be an important contribution. Furthermore, because a single surgeon performed all of the parathyroidectomies, the application of the same principles universally by less experienced surgeons could affect reproducibility.

We describe the ex-MIP approach used in patients with multigland hyperplasia. In an effort to minimize costs and resources, surgeons can use this minimally invasive method, which has been validated in the setting of PHPT due to single-gland disease. The ex-MIP technique allows for individualization depending on the operative findings. This approach can be considered for the vast majority of patients with multigland parathyroid hyperplasia to enhance patient care, decrease costs, and result in excellent outcomes.

Corresponding Author: Robert Udelsman, MD, MBA, Section of Endocrine Surgery, Department of Surgery, Yale University School of Medicine, 330 Cedar St, FMB 102, PO Box 208062, New Haven, CT 06510 (robert.udelsman@yale.edu).

Accepted for Publication: May 23, 2014.

Published Online: September 3, 2014. doi:10.1001/jamasurg.2014.1296.

Author Contributions: Dr Lebastchi and Ms Donovan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lebastchi, Udelsman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lebastchi.

Administrative, technical, or material support: Donovan, Udelsman.

Study supervision: Donovan, Udelsman.

Conflict of Interest Disclosures: None reported.