AHNS Series: Do you know your guidelines? Optimizing outcomes in reoperative parathyroid surgery: Definitive multidisciplinary joint consensus guidelines of the American Head and Neck Society and the British Association of Endocrine and Thyroid Surgeons

2.1 Recommendation 1a

The first step in the evaluation of the reoperative procedures for patients with hyperparathyroidism must include complete biochemical confirmation of primary HPT with hypercalcemia, relative or absolute hyperparathormonemia, and preferably hypercalciuria before reoperation. Level of evidence: 1 to 3, level of recommendation: strong.

The biochemical diagnosis of persistent and recurrent primary hyperparathyroidism is the same as for the initial diagnosis of primary HPT, specifically, hypercalcemia in the presence of a high or inappropriately unsuppressed parathyroid hormone (PTH) level.1, 3, 4

Persistent HPT is defined as hypercalcemia within 6 months of the initial parathyroidectomy, whereas recurrent HPT is defined as hypercalcemia occurring 6 months or more after parathyroidectomy. Persistent HPT is typically due to inadequate surgery, whereas recurrent HPT is usually due to a lack of appreciation for the underlying disease process (either sporadic or genetic; eg, multiple endocrine neoplasia type-1)5, 6 Recurrent HPT in multiple endocrine neoplasia type-1 is an expected outcome after adequate primary initially successful surgery. Patients with recurrent HPT are more likely to have a family history of hyperparathyroidism and/or have had their initial parathyroid surgery performed earlier in life.

Patients who have had parathyroid surgery have typically met one or more of the generally accepted guidelines for surgery. In these patients, indications for surgery have not changed except for the fact that they have had unsuccessful parathyroid surgery and now have new increased risks associated with the reoperative procedure. In those patients who underwent parathyroid surgery, but did not meet any specific guidelines, the decision to consider another parathyroid operation is not straightforward. Asymptomatic patients with primary hyperparathyroidism have been followed for up to a decade without overt evidence of clinically significant disease progression.1

The threshold for reoperative surgery should be higher than for first time surgery; therefore, a quantitative assessment of disease severity is required. Basic assessment of the degree of hypercalcemia (such as a serum calcium >3.00 mmol/L [12.0 mg/dL]) may be complemented by evaluation of kidney function (especially the glomerular filtration rate), renal imaging (abdominal ultrasound or CT for nephrolithiasis/nephrocalcinosis), somatic symptoms (musculoskeletal aches and pains), assessment of bone health (with dual-energy X-ray absorptiometry), and an assessment of cardiovascular risk. Ultimately, thorough and more aggressive imaging than for the initial operation is the basis of successful parathyroid reoperation.7, 8

The overarching cost-benefit analysis of reoperative parathyroid surgery blends the stable issues of disease risk/morbidity and the now increased surgical risk of the more difficult scarred surgical field. The decision to move forward with surgery must be nuanced and shared with the patient and their endocrinologist.

2.2 Recommendation 1b

The diagnosis of HPT must be secured through exclusion of nonparathyroid causes of hypercalcemia and/or hyperparathormonemia. Level of evidence: 2C, level of recommendation: moderate.

Several factors may influence biochemical results and lead to confusion in patient assessment. Vitamin D deficiency and calcium deficiency, particularly if severe, may mask primary HPT, as such patients may present with a normal calcium level. In addition, the 24-hour urine calcium excretion may be low in severely calcium-deficient individuals and the biochemical picture can even mimic secondary hyperparathyroidism. Correction of any documented deficiencies and repeat testing after replacement therapy may reveal the true diagnosis of primary HPT. It must be noted that patients who are vitamin D deficient and are hypercalcemic at the outset should be repleted cautiously; otherwise the hypercalcemia can be exacerbated.

The use of thiazide diuretics and lithium, which may raise PTH and cause mild hypercalcemia, may mimic the diagnosis of primary HPT. These medications should be discontinued when possible and the biochemical evaluation repeated after 6 weeks. Nonparathyroid-mediated hypercalcemia (ie, lymphoma, granulomatous diseases, hyperthyroidism, metastatic bone disease, multiple myeloma, vitamin D toxicity, and milk-alkali syndrome) are distinguished from primary HPT by an appropriately suppressed PTH paired with the elevated calcium. The PTH-related peptide can be assayed when PTH is suppressed in the presence of hypercalcemia. Familial hypocalciuric hypercalcemia must be excluded with a 24-hour urine collection and estimation of the calcium: creatinine clearance ratio. This can be done based on low urinary calcium: creatinine excretion ratio of <0.01. If below 0.01, a mutational analysis of the calcium-sensing receptor and possibly G alpha 11 and AP2S1 may be pursued. Conversely, a renal leak of calcium (hypercalciuria) can result in a compensatory raise in PTH and would cause persistent hyperparathormonemia even after successful surgery for hyperparathyroidism.9

2.3 Recommendation 2

Detailed review of past surgical and pathologic data is essential to optimize surgical success. Level of evidence: 3A-B, level of recommendation: strong.

When a patient is referred for consideration of further parathyroid surgery, it is essential that the multidisciplinary team gathers key patient data. The increased risk of a second exploration through a scarred field requires additional scrutiny to be certain of the diagnosis and to decide whether additional surgery is justified.10 The prior operative notes and pathology reports typically provide important information (although some interpretation may be required), and should be retrieved along with the imaging reports and images obtained before the original operation. This data can be transferred to a surgical planning worksheet (see Figure 1).

Once a decision to operate has been made, the likelihood of single or multiple gland pathology and the likely location of the (missed) lesion(s) need to be determined. If none or only normal parathyroid gland(s) were excised at the first operation, it is likely that the patient still retains a solitary adenoma.11 Therefore, a forensic analysis of the operation notes, the pathology report, and biochemistry results both intraoperatively and perioperatively is fundamental. Particular attention should be paid to which glands were identified, which were removed, and what the pathology was on each excised specimen. From this one might derive the most likely site (quadrant) for the lesion, increase the likelihood of success, and reduce the likelihood of hypoparathyroidism that might result from revision exploration. This analysis also anticipates where scarring is most likely to be encountered.12, 13 The possibility of parathyromatosis should also be considered if there was any suggestion of capsule rupture during the previous surgery. It should be possible to establish from the pathology and imaging reports whether the tissue removed was parathyroid and ascertain its weight and histological characteristics.

2.4 Recommendation 3

Assessment of the patient's current health status and previous surgical complications, if any, must be made before planning for reoperative surgery. Level of evidence: 1-3, level of recommendation: moderate.

Key factors to be considered include known anesthetic risk(s), technical difficulty of additional surgery in a scarred area, and previous complications, such as vocal cord palsy. Finally, these factors need to be brought to bear on the decision on whether the degree of hyperparathyroidism merits reoperation at the present time.19, 20

One must be mindful of interim events that may have occurred that place the patient at greater risk. There may have been progression of existing medical comorbidities from the time of the first procedure. Additional medical conditions may have developed. The persistent or recurrent hyperparathyroidism may have exacerbated or accelerated end organ damage.

2.5 Recommendation 4

Preoperative laryngeal assessment is required in all patients before reoperative parathyroid surgery. Level of evidence: 3A, level of recommendation: strong.

It is imperative to assess the reoperative patient for laryngeal complications that might have occurred as a result of the first parathyroidectomy procedure. These may or may not be heralded by a reported change in voice. Both the Scandinavian Endocrine Registry and the British Endocrine Audit data suggest rates of vocal cord paralysis increase if patients are examined routinely as opposed to only if symptomatic; typically, these rates double.21-23 It is essential in all patients that vocal cord assessment by flexible laryngoscopy be performed as part of their initial evaluation. If there is a vocal cord weakness, this presents a major challenge. If reexploration is confined to the paralyzed or paretic side, perhaps the patient would be exposed to little or no additional risk of ill effects upon their voice from the reoperative procedure. If, however, surgery is conducted on the contralateral side, the only remaining mobile cord is placed at risk. The patient is now at an increased risk for a postoperative bilateral vocal cord paresis that could require a tracheotomy. This possibility must be clearly discussed with the patient with full and written informed consent obtained, which significantly impacts on the core decision making for reoperative surgery.24 The mandatory nature of the laryngeal examination is denoted in multiple major recent endocrine multidisciplinary guidelines, including the AAO-HNS, the ATA guidelines, and the AHNS guidelines.23, 25, 26

2.6 Recommendation 5a

Preoperative imaging of reoperative parathyroid surgical patients is mandatory. Level of evidence: 1-3, level of recommendation: strong.

The importance of obtaining any imaging undertaken before first-time surgery for review cannot be understated. It is common that review by a radiologist experienced in parathyroid imaging will identify a likely location of the disease.3 Thus, localization of the target parathyroid lesion is essential before proceeding with reoperative parathyroid surgery.

2.7 Recommendation 5b

Using the imaging modality that is readily available, most reliable, and cost-effective in a given health system is recommended. This will vary depending on location. Level of evidence: 1-3, level of recommendation: moderate.

2.8 Parathyroid venous sampling and parathyroid angiography

Venous sampling may consist simply of a single sample taken from each internal jugular vein under ultrasound guidance to lateralize disease to one side of the neck or 20 to 30 samples obtained from numerous vessels draining the neck and upper thorax via a femoral venous approach under fluoroscopic guidance. The latter more invasive procedure should only be considered when other cross-sectional imaging studies and scintigraphy are unhelpful.47-50 Combining venous sampling with selective parathyroid arteriography has been shown to improve localization when compared to venous sampling alone.50 Its major advantages are the ability to identify parathyroid glands that cannot be otherwise visualized and to demonstrate venous drainage from neck and upper thoracic vessels that may have been disturbed as a consequence of previous central neck surgery. This study is highly reliant on operator expertise and is potentially associated with serious but uncommon complications, including stroke.

3.1 Recommendation 6

Reoperative parathyroid surgery should be performed in the setting of an identified target gland(s) on preoperative imaging studies. Level of evidence: 3A-B, level of recommendation: strong.

The need for a precision operation is imperative in reoperative parathyroid surgery; therefore, having a specific imaged target is essential.51 Focused exploration and excision based on a preoperative image in conjunction with intraoperative PTH is the most effective way to manage the patient who requires reoperative parathyroid surgery. Unguided bilateral exploration of what can be a significantly scarred central neck is not recommended because it is challenging, often results in a second failure to treat hyperparathyroidism, and risks complications, such as hypoparathyroidism, bilateral vocal cord paralysis, as well as tracheal and cervical esophageal injury.

3.2 Recommendation 7

Parathyroid reoperations are challenging and should be undertaken by experienced surgeons. Level of evidence: 1-3, level of recommendation: moderate.

National datasets revealed lower cure rates with reoperative parathyroid surgery 84% compared to 95% for first time surgery. Although cure rates are lower, complication rates are higher with a 6-fold increase in vocal cord paralysis and a doubling of bleeding rate compared to primary surgery.52 Permanent hypoparathyroidism rates of between 10% and 20% are also described.12

Patients should be assessed and managed on a risk benefit basis. Not all patients with recurrent HPT are surgical candidates. Deciding when to operate is complex and multifaceted, balancing a decrease in cure rate with increased complications compared to primary surgery. Discussion by a multidisciplinary team constitutes good clinical practice.

Morbidity, mortality, length of stay, and cost are inversely proportional to surgical volume.53-55 Institutional experience has been shown to influence operative success; with higher volume institutions having more favorable outcomes.56, 57 For primary HPT surgeons, having an annual volume in excess of 50 cases have better outcomes compared with lower volume surgeons but there are no studies examining this question for reoperative surgery.58

3.3 Recommendation 8

Parathyroids should be approached through nondissected planes avoiding, when possible, most heavily scarred regions. Level of evidence: 1-3, level of recommendation: moderate.

In some cases, the patient has cervical scarring from prior thyroid or anterior cervical spine surgery, whereas others have had prior parathyroid surgery. If the first operation is done by an inexperienced parathyroid surgeon who missed a well localized adenoma, reoperation can be rather straightforward because the surgeon failed to go deep enough in the neck for a superior adenoma or inferior enough within the thymus for an inferior parathyroid adenoma.59-61

A number of approaches are available to the reoperative parathyroid surgeon through less-dissected planes, which can make reoperation more likely to be successful and, at the same time, limiting the risks of complications.

3.3.2 Lateral approach

The lateral approach is ideal for missed superior parathyroid glands in patients who have previously undergone a standard midline approach (see Figure 2).65 One of the most commonly missed parathyroid adenomas is the superior adenoma posterior to the recurrent laryngeal nerve within the tracheoesophageal groove or retroesophageal region. With this approach, a plane is developed between the sternocleidomastoid and the strap muscles on the side in question. The contents of the carotid sheath are then retracted laterally, thus exposing the prevertebral fascia and the tracheoesophageal groove. Typically, the previously undisturbed recurrent laryngeal nerve (RLN) can be easily identified via this approach in a previously undissected plane. The lateral approach may be more difficult after prior low anterior cervical spine surgery as its plane of dissection is similar; however, this alone should not contraindicate the lateral approach.

3.3.3 Superior approach

If preoperative localization identifies an undescended inferior parathyroid gland at the level of the carotid bifurcation, an ultrasound scan can be utilized to determine the most direct route to this missing gland (see Figure 3).65 A small incision can be made in a skin crease directly overlying the gland, and, using a focused approach through previously nondissected planes, the adenoma can be easily identified and removed. Care must be taken to avoid injury to the nearby vagus, superior laryngeal, and hypoglossal nerves.

3.3.4 Inferior approach

An inferior adenoma within the upper portion of the thymus and/or superior mediastinum can be approached through a previously nondissected plane once the original incision is reopened (see Figure 4).65 There is no need to mobilize the thyroid gland on either side. The lower thyroid pole can be exposed, along with the thyrothymic ligament. The thyrothymic ligament can then be separated from the inferior pole and gently retracted upward, often exposing the missed inferior parathyroid adenoma. A map of typical locations for parathyroid discovered at reoperation is presented in Figure 5.8

3.4 Recommendation 9

Intraoperative adjuncts, such as neural monitoring and PTH assay, should be used during reoperative parathyroid surgery. Radioguidance, visible tracers, or ultrasound can be used based on surgeon experience and availability. Level of evidence: 3, level of recommendation: moderate.

3.5 Recommendation 10

During reoperative parathyroid surgery when postoperative hypoparathyroidism is a concern, primary autotransplantation should be considered after frozen section biopsy confirmation. Parathyroid cryopreservation can also be considered if available. Level of evidence: 3-5, level of recommendation: moderate.

There are no data to support the use of IOPTH as a determinant in deciding when to autotransplant. Primary (immediate) autotransplantation should be undertaken with caution owing to the possibility of supernumerary gland(s) in reoperative parathyroid cases.74, 75 This should be optimally reserved for circumstances when it is known that 3 normal glands have previously been excised.76

Parathyroid cryopreservation is the process of freezing and storage of parathyroid tissue with a view to later autotransplantation. It is used when it is envisaged that there may be a need to restore or improve parathyroid function in patients rendered hypoparathyroid after parathyroid surgery. At reoperative surgery, the role for cryopreservation/secondary autotransplantation is controversial owing to the limited success rates for survival of auto grafts (30%-50%).8, 12 The European consensus statement proposes judicious autograft use.21, 22 There is a view that cryopreservation should be restricted to centers that have a large experience in this technique owing to a high failure graft rate (up to 90%).74, 77-79

4.1 Recommendation 11

Nutritional and pharmacologic optimization should be performed in patients refusing or are not candidates for reoperative parathyroid surgery. Treatable metabolic abnormalities should also be addressed in operative patients. Level of evidence: 1-5, level of recommendation: strong.

There are situations in which the patient who was an initial candidate for parathyroid surgery is no longer suitable in the context of recurrent or persistent parathyroid disease. In these situations, medical approaches can be considered as an alternative to surgery.