Minimally Invasive Video-Assisted Parathyroidectomy

Introduction

Bilateral neck exploration (BNE) with the identification of at least four parathyroid glands and the removal of pathologic parathyroid tissue has represented, for several decades, the standard of treatment of primary hyperparathyroidism (PHPT) (see Chapter 56 , Standard Bilateral Parathyroid Exploration). In experienced hands, this approach has a cure rate of more than 95% with minimal morbidity of usually less than 3%.

In spite of the excellent results obtained with BNE, since the early 1980s, less invasive procedures (e.g., unilateral neck exploration [UNE]) have been introduced with the aim to reduce the surgical trauma and the already-low complication rate of parathyroidectomy.

The rationale for a minimally invasive approach for parathyroidectomy derives from the fact that most patients (> 85%) with PHPT have a single parathyroid adenoma, which is potentially identifiable and removable with a focused, selective cervical exploration.

The application of minimally invasive parathyroidectomy (MIP) was initially limited. Only since the early 1990s have these procedures been widely developed; this is because of the evolution of the techniques of preoperative localization (e.g., ultrasound and sestamibi scan) and the introduction of quick intraoperative parathyroid hormone (PTH) assay. Preoperative localization studies allow for a more targeted approach, and the intraoperative PTH assay is able to intraoperatively confirm the success of surgery.

Preoperative Localization Studies

In the case of concordant ultrasonography and scintigraphy, the overall accuracy in parathyroid localization is higher than 95%, whereas in the case of negative localization studies, the likelihood of multiglandular disease (MGD) is higher than 30%.

Obviously, the availability of accurate preoperative localization studies allows the planning of minimally invasive surgical procedures targeting the identified affected gland(s). Imaging studies are concordant in up to 65% of patients with PHPT. It has been well demonstrated that if more than 51% of the patients are eligible for a unilateral exploration or a focused approach, the use of preoperative localization studies is cost effective. A “targeted” approach can also be proposed in cases of positivity of only one localization study. In such a circumstance, the risk of an MGD is about 17%.

Before the advent of the new localization imaging techniques, the sensitivity of preoperative localization studies was 60% to 70% (see Chapter 54 , Guide to Preoperative Parathyroid Localization Testing: Ultrasound, Sestimibi, and 4D CT). For this reason and because of the high success rate of BNE in experienced hands, the guidelines that the National Institutes of Health (NIH) established concerning preoperative localization studies for patients with hyperparathyroidism were not necessary before initial surgery; they should have been performed only in the reoperative cases. The introduction of sestamibi scintigraphy has substantially modified this paradigm. Sestamibi scan is able to localize a parathyroid adenoma in 80% to 95% of cases, with a specificity of about 90% in studies at high-volume centers; however, it may have a sensitivity lower than 50% when interpreted by nondedicated operators. Sestamibi scan is less accurate in cases of MGD (e.g., double adenoma and hyperplasia), which is usually the cause of false-negative results. False-positive results are usually related to the presence of nodular thyroid disease. Single-photon emission computed tomography (SPECT) sestamibi allows a tridimensional reconstruction that can be useful for a spatial localization of the affected gland(s); this gives additional information to the surgeon (see Chapter 54 , Guide to Preoperative Parathyroid Localization Testing: Ultrasound, Sestamibi and 4D CT).

Ultrasound with a high-resolution probe is an accurate, inexpensive, noninvasive, and reproducible procedure; it allows for the precise localization of a parathyroid adenoma in about 80% of the cases, giving additional information about position, size, relationship with adjacent structures, and coexisting thyroid diseases (see Chapter 13 , Ultrasound of the Thyroid and Parathyroid Glands). Even better results are obtained if the ultrasound examination is performed by experienced endocrine surgeons, even as a single localization procedure. It has been demonstrated that surgeon-performed ultrasound had a sensitivity of 82% with a specificity of 90%, compared with radiologist-performed ultrasound, which had a sensitivity of 42% and a specificity of 92%.

Intraoperative PTH Assay

Similar to the progress in the field of preoperative imaging techniques that allowed for targeted approaches, the development and the availability of the intraoperative PTH assay gave surgeons the opportunity to intraoperatively verify the completeness of the surgical resection as an alternative to the complete visualization of all four glands (see Chapter 59 , Intraoperative PTH Monitoring During Parathyroid Surgery). The half-life of intact PTH is 3 to 5 minutes. As a consequence, after the resection of a single adenoma, the removal of all hyperfunctioning parathyroid tissue should be confirmed by a significant reduction of PTH levels. Because rapid techniques have been developed, the intraoperative PTH assay appears to be an attractive method to intraoperatively verify the success of the surgical resection (i.e., a “biochemical” frozen section). The turnaround time has now become very short (less than 10 minutes) and can be performed by laboratory personnel in the operating room using portable machines. Several studies demonstrated a positive correlation between an adequate intraoperative PTH decrease and postoperative eucalcemia.

As a consequence, intraoperative PTH assay emerged as an important adjunct to localizing studies when a focused approach has been planned. By delivering immediate feedback during surgery, intraoperative PTH monitoring allows the surgeon to decide whether unilateral exploration has been successful or if four-gland exploration is necessary. It has been demonstrated that intraoperative PTH increases the cure rate of minimally invasive procedures from 95% to 98%, although it has also been associated with an increase of about 13% of unnecessary BNE.

Most authors agree that intraoperative PTH monitoring is an important, essential, complementary tool in cases of minimally invasive procedures. However, some authors have questioned its usefulness in intraoperative decision making, especially in cases with concordant localization studies that suggest one gland disease. The position statement of the European Society of Endocrine Surgeons suggests intraoperative PTH may be best reserved for patients undergoing targeted parathyroidectomy on the basis of a single preoperative localization study (i.e., sestamibi scan or ultrasonography ) or in cases of discordant preoperative localization studies in which the risk of MGD is higher.

In a retrospective nonrandomized comparative study, Barczyński et al. found that the routine use of intraoperative PTH significantly improves cure rates of minimally invasive, either open or video-assisted parathyroidectomy (VAP), in comparison to open image-guided UNE without intraoperative PTH. This study also suggested that intraoperative PTH can help inform the surgeon in making decisions regarding how to proceed with further neck exploration, especially in cases of only one positive imaging study. Moreover, one paper demonstrated that, at least in an endemic goiter region, intraoperative PTH monitoring seems necessary even in patients with “localized” single-gland disease; abandoning it would significantly increase persistent disease (from 0.9% to 5%).

There are no standardized guidelines about the site, the number, and the timing of blood samples (see Chapter 59 , Intraoperative PTH Monitoring during Parathyroid Surgery). Most authors agree that is preferable to obtain samples from a peripheral vein because samples obtained from internal jugular veins seem less accurate because they are more prone to be affected by variations in PTH levels related to manipulation. Most of the authors agree samples should be obtained during the following times: at baseline (when anesthesia is induced—preincision sample), at the identification of the adenoma (preexcision sample), and at 5 and 10 minutes after the removal of the adenoma (postexcision samples). Some authors prefer to reduce the number of samples to reduce cost; these practitioners obtain samples at preincision and at 15 to 20 minutes postexcision. A later sample (20 to 30 minutes postexcision) may be necessary in cases of inadequate or slow PTH decrease. Moreover, we and others have found that to obtain a higher specificity, it is necessary to extend the sampling period.

Obtaining two “basal” samples (preincision and preexcision samples) is considered necessary because gland manipulation is usually responsible for an increase in PTH levels. In absence of the preexcision sample, postexcision results might be difficult to interpret. To avoid the need for a preexcision sample, some authors propose avoiding any pressure on parathyroid glands before ligating or clipping the vascular pedicle of the adenoma.

The most intriguing and debated point concerns the interpretation criteria. Indeed, no complete and univocal “curative criteria” of intraoperative PTH decline has yet to be established (see Chapter 59 , Intraoperative PTH Monitoring during Parathyroid Surgery). As the criteria for successful surgery, most groups use a 50% reduction from the highest basal level (either the preincision or preexcision sample) 5 to 10 minutes after parathyroidectomy. Others recommend a greater than 50% reduction from the preincision baseline value alone or even an absolute normalization regardless of the preexcision levels. Still, others prefer kinetic analysis of PTH because the PTH half-life can vary from patient to patient. Nonetheless, Carneiro et al. report that the Miami criterion (an intraoperative PTH drop > 50% from the highest basal level at 10 minutes after gland excision) has the highest accuracy (97%) in predicting postoperative calcium levels.

It seems that intraoperative PTH works least well when it is needed the most. Indeed, the role of intraoperative PTH monitoring in identifying patients with MGD is still not clear. Some surgeons report a high incidence of false positives with intraoperative PTH measurements. It has been reported that with an appropriate fall in PTH levels, there is still a 14% to 30% incidence of additional enlarged glands on BNE. In one retrospective study, intraoperative PTH failed to predict the presence of additional abnormal glands in 75% of patients with MGD (6 of 8 patients) when the “50% rule” was applied. Sokoll et al. also reported false-positive results of intraoperative PTH in patients with MGD (i.e., patients with primary, secondary, and tertiary HPT) with a > 50% fall, despite the presence of other enlarged glands. Miller et al. reported that adherence with the 50% rule may lead to several missed cases of MGD; this determination depends, in part, on the initial baseline PTH level. One particular source of false positivity seems to be double adenomas. In a retrospective study on 287 patients, PTH levels decreased more than 50% in 12 out of 15 patients with double adenomas, with a false-positive rate of 57%. Even when used in combination with sestamibi scan and ultrasonography, intraoperative PTH monitoring only correctly predicted the presence of 80% of the double adenomas. In another retrospective study of 20 patients with double adenomas, intraoperative PTH was found to have a false-positive rate of 55% when the 50% rule was applied to predict cure.

Because obtaining a definitive and durable cure is the primary goal for the treatment of patients with PHPT, stricter cure criteria have been variably evaluated and proposed. In this context, the authors of this chapter have evaluated sampling and interpretation criteria that could minimize the rate of false-positive results. We found that to optimize the accuracy of the intraoperative PTH, postexcision samples should be collected 10 and 20 minutes after gland removal. We found that the best three predictors of operative failure and MGD are (1) PTH drop < 50% at 20 minutes, (2) a residual (at 20 minutes) PTH level more than the normal range, or (3) a significant increase of the PTH levels between the sample obtained 20 minutes after gland excision with respect to the 10 minute samples. We evaluated the effectiveness of the new interpretation criteria compared with the Miami criterion in a prospective large series analysis. We found that the application of the new interpretation criteria results in a lower false-positive rate, markedly reducing the risk of missing a MGD. Obviously, this result was obtained at the cost of a higher rate of false-negative results and consequent unnecessary bilateral exploration (15.9% versus 4.8% respectively). A retrospective study comparing different interpretation criteria confirmed that our criteria best predicts MGD even if at the cost of a significantly higher rate of false-negative results.

It is interesting to note that the reported proportion of patients with MGD is considerably lower in recent series using focused approaches combined with intraoperative PTH measurement when compared with series where bilateral exploration was performed using a gross morphologic definition of a hyperfunctioning gland. Irvin et al. also found that using intraoperative PTH measurements as a functional study of disease led to a much lower incidence of MGD, but with an equal cure and recurrence rate. These data suggest that size may not be the most reliable predictor of diseased glands, and some enlarged glands may not be hyperfunctioning. To support this view, a study by Yao et al. demonstrated that the weight of normal parathyroid glands removed at parathyroidectomy may be greater than previously reported in autopsy studies.

Besides interpretation criteria, there are other controversial aspects of the intraoperative PTH assay. In particular, some authors have questioned the cost effectiveness of intraoperative PTH. In a cost analysis study based on a meta-analysis of the literature, intraoperative PTH was responsible for a 4% increase in costs, in spite of a marginal increase in cure rate. However, institution-specific factors seemed to influence the value of intraoperative PTH.

Anesthetic propofol agent was thought to possibly interfere with the PTH assay, but a randomized trial has shown that the PTH assay can be employed during propofol sedation.

In spite of these controversial aspects, intraoperative PTH has emerged as an intraoperative adjunct for parathyroidectomy, especially in cases of targeted parathyroidectomy that rely on a single preoperative localization study, discordant localization studies, and in the reoperative parathyroidectomy.

Intraoperative PTH has been also proposed as an adjunct to intraoperative lateralization of hyperfunctioning parathyroid tissue by samples obtained from internal jugular vein on both sides. It offers also the possibility to measure PTH concentration in fine-needle aspiration (FNA) materials obtained from lesions suspected of being pathologically enlarged parathyroids. A high PTH concentration in the washing fluid of the aspirate has a 100% specificity for a parathyroid lesion and may replace frozen section examination.

Minimally Invasive Parathyroidectomy

The application of endoscopic techniques to neck surgery during the late 1990s resulted in the development of minimally invasive techniques for parathyroidectomy. The general trend toward less invasive procedures for parathyroidectomy is well demonstrated by the results of an international survey, which was conducted in 2000 among the members of the International Association of Endocrine Surgeons (IAES). Fifty-nine percent of the participants used a minimally invasive approach. We feel this percentage may have further increased since that time.

Even if a minority of the authors still consider a standard BNE performed by an experienced endocrine surgeon to be the best treatment for patients with PHPT, others maintain that BNE should be relegated to the past. Clearly, minimally invasive procedures for parathyroidectomy are assuming a more and more important role; in time, they may represent the new gold standard for the treatment of PHPT, at least in its sporadic form.

The consensus statement of the European Society of Endocrine Surgeons (ESES) assumed that even if BNE has excellent results and is always an option for the surgical treatment of PHPT, MIP is a safe and cost-effective procedure to treat selected patients with sporadic PHPT, especially in cases of positive preoperative localization tests. Similarly, the proceedings of the third international workshop on PHPT (Orlando, Florida, 2008) reported that, “unlike previous dogma that mandated surgical identification of both pathologically enlarged and normal parathyroid glands, the current paradigm in many centers is to identify and excise the incident enlarged gland and to confirm operative cure employing a rapid intraoperative PTH assay.” Despite these statements, an audit from the Scandinavian quality register for parathyroid surgery showed that BNE is still performed in two thirds of parathyroid procedures. Indeed, it is true that not all patients with hyperparathyroidism can be treated by a selective minimally invasive approach. Thus we feel that BNE does still maintain a relevant role in the treatment of patients with PHPT (see Chapter 56 , Standard Bilateral Parathyroid Exploration).

Minimally invasive (e.g., focused, targeted, or selective) parathyroidectomy encompasses a number of different techniques, including open approaches (e.g., open minimally invasive parathyroidectomy [OMIP] ), minimally invasive radio-guided parathyroidectomy (MI-RP), VAP, and purely endoscopic parathyroidectomy (EP). As a consequence, there is no strict or unequivocal definition of what an MIP is. The term minimally invasive should be reserved for procedures that allow performance of a traditional operation through access and minimize trauma of the surgical exposure and dissection. BNE is associated with a very low morbidity (< 3%) and high success (> 95%) rates by experienced surgeons. A minimally invasive procedure should obtain at least the same results, with the main advantage of reducing the skin incision and, consequently, allowing better cosmetic results. MIP was thus used to indicate parathyroid procedures performed through a mini-incision usually < 2.5 to 3 cm.

This definition is, at least, reductive, because mini-incision does not necessarily mean a minimally invasive procedure. Moreover, there are several other potential advantages of the targeted parathyroid procedures (i.e., decreased postoperative pain and complications rate), which should be mainly related to the less extensive surgical dissection.

Many studies comparing MIP/focused parathyroidectomy with standard BNE suggest that the focused techniques are safe and at least as good as BNE; these techniques have some advantages such as lower postoperative hypocalcemia, shorter operative time, earlier discharge, better cosmetic results, and reduced postoperative pain. These results were strongly confirmed by five randomized trials with short-term results and one study with long-term results that demonstrated some distinct benefits for MIP over standard BNE (see the Evidence-Based Recommendations section).

Techniques for MIP

Several variants of minimally invasive procedures have been described since the late 1990s, including minimally invasive procedures without endoscope (e.g., OMIP and MI-RP) and with the use of the endoscope (e.g., EP and VAP).