© Springer International Publishing Switzerland 2017Brendan C. Stack, Jr. and Donald L. Bodenner (eds.)Medical and Surgical Treatment of Parathyroid Diseases10.1007/978-3-319-26794-4_21
21. Surgical Management of Known Multiglandular Parathyroid Disease
Otolaryngology/Head and Neck Surgery, The Portland VA Health Care System and Oregon Health and Science University, 3181 SW Sam Jackson Park Road, MC PV-01, Portland, OR 97239, USA
Daniel Clayburgh (Corresponding author)
The majority of patients presenting with hyperparathyroidism have a single adenoma responsible for elevated parathyroid hormone levels. However, in about 10–15 % of cases, two or more parathyroid glands are involved in the disease process. Thus, any surgical intervention must address all diseased glands in order to provide benefit to the patient. While multiglandular disease is commonly sporadic, multiple other factors may lead to gland enlargement, including drugs such as lithium, renal disease, and genetic disorders such as multiple endocrine neoplasia; in these instances significantly more investigation and/or treatment is required than in those patients with sporadic disease. Thus, the clinician must carry a heightened level of suspicion for other causes of disease when multiglandular disease is recognized.
Given that preoperative imaging and localization studies are often not accurate in predicting the glands involved in multiglandular disease, bilateral parathyroid exploration is often required in these cases. The parathyroid surgeon must have a thorough understanding of the anatomy and potential ectopic locations of the parathyroid glands, as well as the potential locations of supranumerary glands that may sometimes be encountered. A full discussion of parathyroid anatomy is contained elsewhere in this book and falls outside the scope of this chapter. However, multiple options for the extent of surgery are available to deal with multiglandular disease, and may be tailored specifically to the individual patient and underlying disease process. This underscores the importance of a thorough preoperative evaluation and determination of the underlying cause of multiglandular hyperparathyroidism.
Basic Surgical Techniques in Multiglandular Parathyroid Disease
Fundamentals of Parathyroid Exploration
An understanding of parathyroid anatomy is paramount in bilateral parathyroid exploration for multiglandular disease. The surgeon must have knowledge of the typical locations, ectopic locations, and parathyroid blood supply. This has been thoroughly discussed in earlier chapters. When performing bilateral exploration, each gland should be assessed to determine if it is normal or abnormal in size, and its vascular blood supply should be identified. One should resist the urge to excise the gland as soon as it is identified and exposed. It is important to treat every parathyroid gland as if it is the last one left in the patient.
Once identified, a small fragment of the gland should be biopsied at the tip of the gland away from the polar vessels to confirm parathyroid tissue. If four gland exploration is planned, unless the intent is for total parathyroidectomy, all four glands should be identified first and the decision for which gland will be left in situ should then be made after assessing viability and location. If the surgical strategy is for subtotal parathyroidectomy, approximately 5 × 10 mm size of the most viable appearing gland should be left in situ. A healthy parathyroid should not be pale, which indicates arterial insufficiency, nor dusky, which is indicative of venous congestion. When choosing between viable parathyroid glands to leave in situ, it is best to leave the inferior glands, as they are located more anterior and thus more accessible for re-excision with less risk to the recurrent laryngeal nerve in the event of recurrent hyperparathyroidism
Total Parathyroidectomy with Autotransplantation
Total parathyroidectomy and autotransplantation is appropriate for patients with secondary hyperparathyroidism who are not candidates for transplant, since regrowth of parathyroid tissue left in the neck is likely to occur from the stimulus of chronic uremia. Re-implantation is typically in the brachioradialis muscle, ideally the nondominant arm; however, these patients often have an arteriovenous shunt for dialysis access in their nondominant arm. Often a suitable site for reimplantation can be located at a point in the arm far from the shunt, but if that is not possible, reimplantation will need to occur in the contralateral arm.
Permanent hypoparathyroidism is a devastating complication of parathyroidectomy. This risk is significantly higher in patients undergoing subtotal or total parathyroidectomy. Despite the use of autotransplantation after total parathyroidectomy, a small percentage of patients may not have full function of the autotransplanted tissue and experience hypoparathyroidism. To combat this complication, the technique of cryopreservation was developed in the 1970s . This technique involves preserving one or more resected parathyroid glands at -80 °C for later autotransplantation. This is described in more detail in another chapter. Autotransplantation after cryopreservation generally has a lower rate of success than primary autotransplantation, with graft success rates ranging from 17 to 83 % . While this technique is widely used as “insurance” against poorly functioning autografts, given the poor functioning of cryopreserved tissue and the relative rarity of permanent hypoparathyroidism after parathyroidectomy, some authors have called into question the necessity of this procedure in most circumstances .
Surgical Approach to Specific Causes of Multiglandular Parathyroid Disease
Sporadic Primary Hyperparathyroidism
Primary hyperparathyroidism is relatively common, with an estimated incidence of up to 2.1 % in postmenopausal females . Most of these cases are relatively mild and may be managed medically; only a small percentage of patients require surgical intervention . Symptomatic hyperparathyroidism (nephrolithiasis or symptomatic hypercalcemia) should undergo surgery. The vast majority of patients are asymptomatic; in these patients, current guidelines recommend parathyroidectomy for serum calcium levels 1.0 mg/dl or more above the upper limit of normal, estimated glomerular filtration rate <60 ml/min, bone density at the hip, distal radius, or lumbar spine >2.5 standard deviations below peak bone mass (T score <−2.5), 24 h urine calcium >400 mg/day, nephrolithiasis on radiograph, ultrasound, or CT, or patient age <50 years . In sporadic primary hyperparathyroidism, multiglandular disease occurs in 10–15 % of patients. Multiglandular disease more often manifests as mild hypercalcemia; severe hypercalcemia is usually due to an adenoma . Multiglandular disease is often encountered in younger male patients with nephrolithiasis despite only mildly elevated serum calcium . Thus, patients with only mild elevations in serum calcium but who are otherwise indicated for surgery should be approached with caution, and are likely best treated by those with specialized experience.
The underlying cause of sporadic hyperparathyroidism remains unknown, although some inroads have been made in understanding the molecular pathology of this disease. Alterations in cyclin D1, a regulator of the retinoblastoma protein and cell cycle control, were the first described mutations associated with hyperparathyroidism . Sporadic mutations in the MET-1 gene have also been implicated in the development of this disease . The presence of certain polymorphisms in the vitamin D receptor has been linked to mild primary hyperparathyroidism . However, whole exome sequencing of hyperplastic parathyroid glands showed a wide heterogeneity in mutations present, suggesting a more complex, multifactorial pathogenesis for this disease . Histologically, the parathyroid glands in patients with multiglandular disease demonstrate nodular chief cell hyperplasia. This is typically not symmetric among glands; usually only two or three glands are enlarged, and these nodules appear similar to small adenomas. In fact, these glands are often indistinguishable from multiple adenomas . In most patients with multiglandular disease, two glands are enlarged; cases with three or four enlarged glands are more uncommon [7, 13]. Obvious four gland enlargement is more likely to represent water clear cell hyperplasia or patients with unrecognized MEN1 syndrome.
Preoperative imaging with ultrasound, 4-D CT, and/or sestamibi scanning is very useful in detecting adenomas but is typically not sensitive enough to adequately detect multiglandular disease. Thus, in the absence of clear localizing studies, the surgeon must be prepared for exploration of all four parathyroid glands. Generally in cases of multiglandular sporadic hyperparathyroidism, only the enlarged glands are excised, and the normal-appearing glands are left intact . In patients with double adenomas, two glands are excised; in those with three or four enlarged glands, subtotal parathyroidectomy is recommended . A cervical thymectomy should also be considered when multiple abnormal glands are seen, as supernumerary glands are often found within the thymus. Water-clear cell hyperplasia may be discovered during the procedure; this manifests as four gland disease with exceptionally enlarged, brownish parathyroid glands. In these cases the parathyroid tissue does not function well, thus a much larger remnant should be preserved after subtotal parathyroidectomy .
Lithium therapy is a common treatment for bipolar disease, and patients are often on this medication for many years. Lithium may cause hypercalcemia due to hyperparathyroidism in 5–50 % of patients [17, 18]. The exact mechanism by which this occurs remains unclear; lithium appears to antagonize the calcium receptor in parathyroid cells, thereby reducing calcium-induced PTH suppression, or it may directly stimulate PTH release from the parathyroid cell . Hypercalcemia typically develops after many years of lithium treatment, and is characterized by mild hypercalcemia with only moderately elevated PTH levels. In a small subset of patients, hypercalcemia may develop rapidly after the initiation of lithium therapy. This is typically due to unrecognized primary hyperparathyroidism unmasked by lithium therapy; generally an adenoma may be identified in these patients and cured with surgery.
Withdrawal from lithium therapy will often correct hypercalcemia; however, not all patients are able to discontinue therapy. While medical management is possible, in the long term surgery is often more efficacious and cost effective. Multiglandular disease is more common than in sporadic hyperparathyroidism, with rates ranging from 25 to 56 % [20–23]. Because of this fact, a four-gland exploration has been the gold standard for surgical treatment for many years. Excision of any abnormally-sized gland with preservation of normal appearing glands is typically sufficient for cure. With advances in preoperative localization and intraoperative PTH (IOPTH) assays , many are now moving to minimally invasive parathyroidectomy in those patients where a single abnormal gland can be localized . However, standard criteria for a postoperative decrease in IOPTH level to <50 % of baseline do not always adequately predict cure in these patients [21, 23]. False positive IOPTH result occurs when IOPTH reduces more than 50 % from pre-excision level however another remaining enlarged gland can subsequently hypersecrete. Long-term cure rates with surgery generally exceed 80 % .
Parathyromatosis is a rare cause of recurrent or persistent hyperparathyroidism and is exceeding difficult to manage. It consists of numerous islands of hyperfunctioning parathyroid tissue scattered throughout the neck and mediastinum. Two etiologies have been proposed for this: either intraoperative spillage and seeding of parathyroid tissue throughout the operative field during parathyroidectomy or hyperplasia of preexisting embryological rests of parathyroid tissue. Although a few early reports of scattered hyperfunctioning parathyroid tissue at primary surgery exist to support the latter theory of pathogenesis, most surgeons believe that parathyromatosis is due to intraoperative spillage during parathyroidectomy [25, 26]. Occasionally parathyromatosis may be diagnosed on localization studies such as ultrasound [27, 28], but it is more commonly discovered intraoperatively. Surgical management of this condition is usually unsuccessful; it is often difficult to identify all nodules of parathyromatosis, and these nodules are typically adherent to old surgical scar or other structures making excision difficult. If discovered during surgery, removal of obvious parathyromatosis or a formal unilateral level VI dissection for unilateral disease may be attempted, but medical management will often be required over the long term.
Multiple Endocrine Neoplasia Type I
MEN-1 is a relatively rare autosomal dominant disease affecting approximately 1 in 30,000 people . This syndrome is manifested by tumors of the pancreas (neuroendocrine pancreatic tumors), pituitary, and parathyroid glands. Other tumors associated with MEN-1 include lipomas, carcinoid tumors, facial angiofibromas, pheochromocytomas, thyroid neoplasms, and adrenocortical adenomas . MEN-1 is caused by mutations in the MEN-1 gene on chromosome 11q13 [31, 32]. This gene encodes the menin protein, which is involved in regulation of transcriptional regulation, although its exact function remains unknown. It is believed to function as a tumor suppressor and leads to tumor formation via the “two-hit” hypothesis: patients with MEN-1 possess a germline mutation in one of the two copies of MEN1; when a random mutation occurs in the second copy in a cell, this initiates clonal expansion and tumor formation.
More than 1000 germline MEN1 mutations have been identified, which account for 70–90 % of families with MEN-1 [29, 33, 34]. Unlike MEN-2A, this large number of mutations has prevented the development of clear genotype-phenotype correlations; at this point mutational analysis cannot predict tumor distribution, disease severity, or age of onset . Despite this, families may demonstrate relatively consistent disease phenotypes. Thus, genetic testing remains useful in order to follow patients prospectively for close testing, or to rule out disease in subjects within families with known mutations. However, negative genetic testing does not exclude the disease in potential probands, as even full MEN1 gene sequencing detects only 70–90 % of mutations in patients with classic MEN-1 features .
Current guidelines recommend testing for MEN1 mutations in several situations: an index case with two or more MEN-1-associated endocrine tumors, first degree relatives of MEN1 mutation carriers, or in patients with possible atypical MEN-1, development of a single MEN-1-associated tumor such as islet cell tumors, gastrinoma, or multiglandular parathyroid disease at a young age, or two or more MEN-1-associated tumors not part of the classic triad (pancreas, pituitary, parathyroid) . Testing for MEN1 mutations in first-degree relatives of known MEN1 carriers is particularly important, as it will indicate those individuals that should be screened closely for MEN-1-associated tumors and those that do not need extensive testing and may be relieved of the anxiety of possible tumor development. When possible, testing should occur in children before 10 years of age, as MEN-1 tumors have been reported in children as young as 10 . See the chapter “Familial hypocalcuric hypercalcemia (FHH) genetic testing and counseling for hyperparathyroidism” for more information.
Primary hyperparathyroidism is the most common feature of MEN-1 and occurs in up to 90 % of patients . MEN-1-associated hyperparathyroidism accounts for approximately 2–4 % of all cases of primary hyperparathyroidism, and is characterized by a particularly aggressive multiglandular disease [38, 39]. Given the “two-hit” hypothesis regarding the pathogenesis of MEN-1, the parathyroid disease in this condition is typically asymmetric and multiglandular. As the “second hit” is unlikely to occur synchronously in two parathyroid glands, gland enlargement occurs at different times. Normal appearing parathyroid glands are not uncommonly reported in MEN-1 patients, although the frequency of finding normal glands decreases with age, and the “second hit” is highly likely to occur over time [33, 40]. Onset of hyperparathyroidism in MEN-1 patient is usually much earlier than in patients with sporadic hyperparathyroidism, typically in the third or fourth decade; by age 50 virtually all MEN-1 patients will develop hyperparathyroidism [38, 40]. The degree of bone mineral loss in hyperparathyroidism patients is also typically more severe than in patients with sporadic hyperparathyroidism.
Patients with known MEN1 mutations should undergo yearly screening for parathyroid disease with measurement of serum calcium and parathyroid hormone levels . Once detected, localization studies such as ultrasound and sestamibi are not particularly useful, as all glands are usually affected and a bilateral neck exploration is needed. However, if an ectopic gland is suspected, preoperative imaging may be useful to guide the exploration. The indications for parathyroidectomy in MEN-1 are no different than for patients with sporadic hyperparathyroidism: symptomatic patients should undergo surgery, while asymptomatic patients may undergo surgery based on previously discussed guidelines. However, given the progressive and aggressive nature of parathyroid disease, the timing of surgery should carefully consider surgeon experience, patient preferences, and availability of long-term calcium monitoring facilities prior to undertaking surgery in asymptomatic patients. Given the high likelihood of future revision surgery, particularly in young MEN-1 patients, it has been suggested to reserve surgery for patients with symptomatic hyperparathyroidism, and carefully monitor asymptomatic patients for symptoms and complications . Calcimimetics may be used in patients where surgery is contraindicated, or has failed to cure the hyperparathyroidism .
Given the progressive nature on hyperparathyroidism in MEN-1, permanent cure of hyperparathyroidism is typically not possible. Thus, the aim of surgery should be to minimize the risk of permanent hypoparathyroidism while providing the longest possible recurrence-free interval. In the past, parathyroidectomy removing only the enlarged glands and leaving one or more intact parathyroid glands has been attempted for MEN-1 patients. This approach was found to lead to unacceptably high rates of recurrence, ranging from 23 to 61 % in various studies [42–44]. When compared to subtotal or total parathyroidectomy, patients undergoing less than subtotal parathyroidectomy had a significantly shorter median recurrence-free survival (7 vs. 16.5 years) and a substantially lower rate of 10-year recurrence free survival (37 % vs. 61 %) . Thus, this approach has largely been abandoned for either subtotal parathyroidectomy or total parathyroidectomy with autotransplantation.
In most MEN-1 patients undergoing initial surgery, subtotal parathyroidectomy is the preferred operation. The recurrence rates of hyperparathyroidism in studies of this procedure are generally dependent on the length of follow up; as all parathyroid tissue in these patients harbors the MEN1mutation, any residual parathyroid tissue is likely to become hyperplastic if given sufficient time. In fact, in one study the length of follow up time was one of the best predictors of recurrence in multivariate analysis . Recurrence rates after subtotal parathyroidectomy have been reported between 13 and 35 % after several years of follow up [45–47]. Comparison of this technique with less than subtotal parathyroidectomy and total parathyroidectomy have shown the rate of recurrence is significantly better than procedures removing less than a subtotal parathyroidectomy, but somewhat increased from total parathyroidectomy. However, the rate of severe hypocalcemia is significantly increased with total parathyroidectomy, (46 % vs. 26 % with subtotal parathyroidectomy) requiring chronic calcium supplementation and careful serum calcium monitoring . Thus, in order to minimize harm to patients, a subtotal parathyroidectomy has become the procedure of choice during initial surgery for MEN-1 hyperparathyroidism.
Bilateral neck exploration is required, and all four parathyroid glands are identified. The most normal-appearing gland of the four should be selected to remain in the body, ideally leaving equivalent of a normal size gland (approximately 40–50 mg of tissue or less, or less than double the size of a normal gland). If partial resection of a gland is needed, a hemoclip should be placed across the gland and sharp division performed just distal to this clip; this will both help to prevent seeding of hyperplastic parathyroid cells into the nearby tissues and also facilitate localization of the gland if reoperation is needed. Once this has been performed and the parathyroid remnant appears well-vascularized, the remaining three abnormal parathyroid glands are resected. A cervical thymectomy should also be performed during this procedure, as there is a high incidence of ectopic parathyroid glands or tissue that may lead to future recurrence. Up to 30 % of MEN-1 patients have ectopic or supranumerary parathyroid glands, and the removal of the thymus may identify up to 50 % of these ectopic glands . Preoperative imaging with CT imaging and/or Sestamibi is also useful to identify any ectopic glands. Once all other parathyroid glands have been resected, an intraoperative parathyroid hormone level may be obtained; if the parathyroid hormone level becomes undetectable, autotransplantation of parathyroid tissue into the nondominant forearm may be considered; however, this is not routinely required.
While total parathyroidectomy may not be routinely utilized as the initial procedure for MEN-1, there are situations where it is the preferred procedure. In patients with four markedly enlarged parathyroid glands, this procedure obviates the need to trim a diseased parathyroid within the neck, with associated risk of later parathyromatosis. This is also the preferred procedure during revision surgery, as further surgeries in the neck are likely to be complicated by scarring and adhesions. Total parathyroidectomy involves removal of all four parathyroid glands from the neck. The most normal-appearing gland is then selected for autotransplantation. Approximately 60–80 mg of tissue is minced and then placed into small pockets within the muscle of the nondominant forearm. Thus, recurrent disease within the forearm can be treated with excision of the parathyroid autograft under local anesthesia, obviating the need for general anesthesia for revision cervical surgery. The site of the autografts should be marked with hemoclips (Figure 1), and information regarding the number of clips as well as their precise anatomic location should be dictated in the operative note to facilitate excision of the autograft.
Reported results of total parathyroidectomy are often quite good, with many authors demonstrating zero recurrences within the neck . As discussed previously, overall recurrence rates are also somewhat better than those seen after subtotal parathyroidectomy. However, the major drawback to this procedure is the high likelihood of severe and persistent hypocalcemia after surgery. While the autografts typically functional in approximately 4 weeks, the rate of functional return is variable. In one series, up to 40 % of autografts remained nonfunctional nearly 3 years after surgery, requiring prolonged hypocalcemia treatment and monitoring . Other authors have reported somewhat better results, although a hypocalcemia remained a significant problem in a number of patients [45, 47]. Given these risks, this procedure is typically reserved for recurrent or particularly problematic cases of MEN-1-associated hyperparathyroidism.
Multiple Endocrine Neoplasia 2A
MEN-2A is an autosomal dominant disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Medullary thyroid cancer occurs in 70–100 % of MEN-2A patients; pheochromocytomas occurs in about 50 % of patients, and hyperparathyroidism is seen in 20–30 % of patients . Other uncommon manifestations of this syndrome include Hirshprung’s disease and cutaneous lichen amyloidosis. MEN-2A is caused by mutations in the RET protooncogene, and occurs in approximately 1 in 30,000 people . Over 50 different point mutations have been identified in the RET gene, and current genetic tests can detect nearly 100 % of mutation carriers . There is a strong correlation between individual RET mutations and disease phenotype, including age of onset, medullary thyroid carcinoma aggressiveness, and the presence of other endocrine abnormalities.
Based on genotype-phenotype associations, the American Thyroid Association created a risk stratification system based on the genetic mutation present and its correlation to the risk and aggressiveness of medullary thyroid carcinoma, with specific diagnostic and treatment recommendations based on this risk stratification . While this risk stratification is primarily concerned with medullary thyroid carcinoma, genotype correlations to hyperparathyroidism are also well established. Primary hyperparathyroidism is most common in patients with the C634R mutation, although it is less commonly seen in several other genotypes, including E768D, S649L, L790F, Y791F, V804L, V804M, S891A, C609F/R/G/S/Y C630R/F/S/Y, and others . Thus, knowledge of a patient’s specific mutation may alter long-term screening for hyperparathyroidism and the approach to initial thyroidectomy.
Hyperparathyroidism in MEN-2A is generally mild, with only slight elevation of serum calcium and infrequent symptoms [39, 54]. The median age of onset is around 38 years; current guidelines recommend that yearly screening with serum calcium and PTH measurements begin at 8 years of age in patients with C634R and C630R/F/S/Y mutations, and by age 20 in all other MEN-2A patients . Similar to other familial forms of hyperparathyroidism, MEN-2A-associated hyperparathyroidism is generally considered to be multiglandular; however, adenomas and asymmetric gland enlargement are much more common than in MEN-1. In one study, 43 % of MEN-2A patients had a single adenoma and 45 % had multiglandular hyperplasia . Ectopic or supernumerary glands may be present, but are not as common as in MEN-1.
The indications for parathyroidectomy in MEN-2A are the same as in sporadic hyperparathyroidism or MEN-1. However, given the prevalence of medullary thyroid carcinoma, most patients with MEN-2A undergo total thyroidectomy, often at a young age, along with possible central compartment dissection. The high likelihood of previous neck surgery in MEN-2A patients therefore makes parathyroidectomy much more difficult. In the occasional patient that has not had prior surgery, or where hyperparathyroidism is discovered prior to a planned thyroidectomy, a four-gland exploration is recommended at the time of thyroidectomy. Given the much higher incidence of single or double adenoma and the milder course of MEN-2A-associated hyperparathyroidism, the primary focus of surgery should be preservation of parathyroid function, with removal of only grossly abnormal glands. The location of other parathyroid glands may be marked with surgical clips, as these may be useful in case later reoperation is necessary.
In patients that have had previous thyroidectomy, the previous operative records should be carefully reviewed to determine which parathyroid glands were identified and/or removed at surgery, to avoid unnecessary dissection. Given the difficulty of parathyroid exploration in a previously dissected thyroidectomy bed, preoperative localization studies should be utilized, and a more directed surgical approach for only those glands found to be grossly abnormal on imaging may be employed. Four-dimensional CT scans have been shown to be superior to both ultrasound and sestamibi scans in localizing abnormal glands, particularly in the reoperative setting .