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Standard Bilateral Parathyroid Exploration
Introduction to Chapter 56, Standard Bilateral Parathyroid Exploration.
Modern management of parathyroid disease has evolved with the influence of several fundamentally new and important factors. First is the reality that primary hyperparathyroidism (PHPT) is no longer a rare endocrine disorder, but the most common cause of hypercalcemia in the outpatient population; it has an estimated prevalence of 1 in 500 women and 1 in 2000 men. The incidence increases with age and is 2 to 3 times more common in women. A second and related factor is a higher prevalence of asymptomatic PHPT, where a clear biochemical diagnosis of parathyroid disease exists without noticeable symptoms or clinically detectable consequences, such as bone density loss or kidney stones. An additional reason that more patients are being diagnosed in an asymptomatic phase of the disease is because calcium has become a routine component of automated chemistry panels; this helps lead to incidental detection of symptomatic hypercalcemia. Conversely, more practitioners are also recognizing the need to screen patients with osteoporosis, osteopenia, and kidney stones for underlying PHPT; practitioners use not just calcium screening, but a panel that includes calcium, intact parathyroid hormone (PTH), and 25-hydroxyvitamin D levels (see Chapter 53 , Primary Hyperparathyroidism: Pathophysiology, Surgical Indications, and Preoperative Workup). Finally, perhaps the most visible changes in the landscape of parathyroid disease management are the paradigm shifts in the preferred operative approach. After many years of standard bilateral explorations, there was a shift in the late 1990s to a more focused approach: the exploration of a single site of suspected parathyroid gland abnormality. Many parathyroid surgeons adapted this as the favored initial approach to parathyroid surgery, guided by radiological studies and intraoperative PTH measurement (see Chapter 54 , Guide to Preoperative Parathyroid Localization Testing; Chapter 57 , Minimally Invasive Single Gland Parathyroid Exploration; Chapter 58 , Minimally Invasive Video-Assisted Parathyroidectomy; and Chapter 59 , Intraoperative PTH Monitoring during Parathyroid Surgery). More recently, however, the bilateral exploration appears to be back in favor among endocrine and head and neck surgeons. Image-directed, focused parathyroid surgery is still frequently used in appropriate patients, but the limitations of preoperative localization and intraoperative PTH levels in reliably identifying multi-gland disease is well-appreciated, and the pendulum appears to be swinging back to the middle ground of selected, focused operations and a low threshold to consider a bilateral exploration.
This technique of achieving the surgical cure of PHPT was the original operative approach preferred from the 1920s through the late 1990s . At its essence, this approach can be defined as the exploration and examination of all parathyroid glands bilaterally with appropriate resection of diseased glands. It is imperative to recognize that “conventional” or “bilateral” parathyroid procedures are not obsolete; they remain essential and are at the core of successful parathyroid surgery. Bilateral parathyroidectomy will remain integral to the surgical treatment of PHPT; for appropriate patients, it is the ideal initial operation. It is also important to recognize that bilateral parathyroid examination can be performed in a minimally invasive manner. This approach requires a thorough understanding of parathyroid gland anatomy, embryology, and of specific indications based on clinical presentation, parathyroid imaging, and intraoperative findings. In this chapter, we provide the rationale for and method of bilateral parathyroid exploration, illustrated with relevant clinical examples and a strategy for addressing the problematic circumstance of finding a “missing gland” (see also Chapter 55 , Principles in Surgical Management of Primary Hyperparathyroidism).
Anatomy and Embryology Relevant for Bilateral Parathyroid Exploration
There are typically four parathyroid glands in most individuals; thus bilateral exploration ideally aims to identify all four (see Chapter 2 , Applied Embryology of the Thyroid and Parathyroid Glands). A large autopsy study identified four parathyroid glands in 84% of human cadavers, ≥ 5glands in 13%, and only three parathyroids in 3%. Supranumerary parathyroids are most often located in the thymus. The possibility of having an unusual number or location of parathyroid glands has a direct effect on the success of parathyroid surgery and the potential need for bilateral parathyroidectomy, yet it remains difficult to predict such anomalies reliably. The potential for missed ectopic or supranumerary parathyroids and persistent or recurrent hyperparathyroidism (HPT) should be discussed with patients before surgery to properly inform expectations of surgery.
The key aspects of parathyroid anatomy and embryology to adapt to bilateral parathyroidectomy are illustrated in Figures 56.1 to 56.3 . Normal parathyroid glands are approximately 5 to 6 mm in greatest dimension, weigh 15 to 35 mg, and can be inconspicuous with their orange-tan color embedded or flattened within a surrounding yellow fatty tissue envelope. The appearance of parathyroids can be variable even when they are biochemically functioning normally. When diseased, parathyroid glands may display variable morphological changes in size, shape, texture, and firmness. Abnormal parathyroids are generally fuller in all dimensions, have a darker brown or reddish-brown color, do not compress easily, or are significantly firm when gently probed. They may have an irregular and lobular shape, more prominent vascular pedicles, or a plexus of vasculature. Glands of patients with secondary and tertiary HPT may be sclerotic and light in color from fibrosis.
In cases of borderline abnormal appearance, it is helpful to determine in vivo parathyroid weight before excision of the parathyroid. This can be readily done without removing the gland by measuring parathyroid length (L), width (W), and height (H) using a small ruler or micrometer device. Because most glands are oval, calculating the volume of an ellipsoid using sizes in millimeters (mm) estimates parathyroid gland weight in milligrams (mg): (weight [mg] ≈ L × W × H mm 3 ×½). We have observed that the metric of the total volume of diseased glands (TVDG) is statistically the same, whether the surgical findings are single- or multigland parathyroid disease. In other words, the size of a typical single adenoma will be similar to the additive size (by volume or weight) of both double adenomas or of four hyperplastic glands. This implies that there ought to be caution for the likely presence of multigland disease—and therefore the need for bilateral parathyroid exploration—when only a mildly enlarged parathyroid is encountered first. Even when imaging studies suggest a single site of parathyroid disease and intraoperative PTH falls appropriately, a parathyroid gland that is 75 to 200 mg in size will rarely be a single adenoma (see Chapter 59 , Intraoperative PTH Monitoring during Parathyroid Surgery). There is ongoing interest and some controversy in defining what truly constitutes an abnormal parathyroid and whether this is a matter of purely morphological form, biochemical function, or a combination of both features (see Chapter 55 , Principles in Surgical Management of Primary Hyperparathyroidism).
Embryologically, the upper parathyroids develop from the fourth branchial pouch and migrate caudally with the thyroid, whereas the lower parathyroid glands derive from the third branchial pouch and migrate with the thymus. The upper parathyroid glands have a narrower area of distribution, are fairly reliably positioned in the perithyroidal fat posterior to the superior pole of the thyroid gland, and they are near the path of the recurrent laryngeal nerve (RLN) as it enters the cricothyroid muscle (see Figure 56.2 ). In contrast, the lower parathyroids are more widespread around the lower pole of the thyroid gland, thyrothymic ligament, and pretracheal fat. Symmetry is usually present between parathyroid locations in the left and right sides of the neck, and this can strategically be used when trying to locate parathyroid glands. Double parathyroid adenomas, however, do not have a uniform or random distribution pattern; when only two glands are enlarged and histologically hypercellular, they tend to be on opposite sides of the neck and may tend to the upper parathyroids; this pattern is designated “fourth pouch disease.” ( Figure 56.4 ).
Additional clues for parathyroid location can come from observing the patterns of vasculature in and around the expected parathyroid region. Both parathyroids typically derive some blood supply from the inferior thyroid artery. In relation to the path of the main trunk of this artery as it nears the thyroid, upper parathyroids are cranial and deeper; lower parathyroids are caudal, anterior, and medial. Unusually curved or extra branching patterns of the artery may alert to abnormal parathyroids found hanging at the ends of those branches, sometimes several centimeters away from the thyroid capsule. Within their fatty envelope, a normal parathyroid will have a leaflike branching pattern of the vascular pedicle. This is a helpful contrast to lymph nodes, fat or thymic tissues (that have no visible vascular pattern), and abnormal parathyroids whose vascular pedicle may be exaggerated. Being alert to these subtle morphological features can expedite finding parathyroids during bilateral exploration.
Migratory distribution of the parathyroids can lead to ectopic locations within the following locations: the thymus, the sheath encompassing the carotid artery, the jugular vein, the vagus nerve (even in high cervical locations), the retroesophageal region, and even within the thyroid. Some, but not all, of these areas can be accessed via the usual cervical incision during bilateral parathyroid exploration. Recently, Perrier et al. proposed novel nomenclature to further classify cervical parathyroid adenomas into regions relevant for parathyroid exploration (see Chapter 57 , Minimally Invasive Single Gland Parathyroid Exploration). Ectopic parathyroid locations in the anterior mediastinum, other deeper regions of the mediastinum, and even the pericardium require alternate surgical approaches, which often require collaboration with thoracic surgeons.
The Rationale for Bilateral Parathyroid Exploration
The cornerstones of successful parathyroid surgery are correct initial diagnosis of parathyroid disease and clear articulation of treatment goals based on an individual’s clinical profile of parathyroid disease. Although, on the surface, it may appear that these processes are the same whether parathyroidectomy is approached as a focal or bilateral exploration, there are nuances that affect the rationale for bilateral exploration.
Diagnosis
Bilateral parathyroid exploration principally involves patients with PHPT, although it is also needed in those who have secondary or tertiary HPT from renal disease. The latter diagnoses are covered in detail in separate chapters (see Chapter 60 , Surgical Management of Multiglandular Parathyroid Disease; Chapter 61 , Surgical Management of Secondary and Tertiary Hyperparathyroidism; and Chapter 62 , Parathyroid Management in the MEN Syndromes). Traditionally, the diagnosis of PHPT has rested on the demonstration of simultaneously elevated serum total or ionized calcium with elevated intact PTH in the setting of normal or high calcium excretion in the urine. With this combination of findings, the diagnosis of PHPT is practically definitive. In part, this is because modern measurements of PTH detect the intact molecule, reflecting the entire protein derived from the parathyroid glands and essentially eliminating confounding diagnoses from ectopic sources of PTH, such as tumors producing PTH-related peptide (PTHrp). The rare hereditary condition of benign familial hypercalcemic hypocalciuria (BFHH) is excluded by the finding of normal or high levels of calcium in a 24-hour urine collection.
Approximately 10% of patients will have unusual biochemical presentations that do not fit these classical diagnostic criteria but are nonetheless found to have PHPT. There are at least two atypical versions of the disease. Normocalcemic PHPT manifests with normal total serum calcium but high PTH and has been relatively well appreciated. Despite borderline laboratory values, patients with normocalcemic hyperparathyroidism may suffer from kidney stones, osteoporosis, and bone fractures. Patients with the other form of PHPT have high calcium levels but normal PTH. Diagnosis is somewhat easier if PTH values are “inappropriately” high-normal for the degree of hypercalcemia (40 to 60 pg/mL on a scale where 60 pg/mL is maximal reference range) but can be less clear when values are as low as 5 to 15 pg/mL.
Box 56.1 provides a recommended diagnostic workup for PHPT and strategies to clarify the diagnosis in challenging scenarios. It is advisable to obtain a baseline bone density assessment with a dual energy x-ray absorptiometry (DEXA) bone scan, especially if this did not precede referral of the patient to the surgeon. Urinary calcium excretion lower than 50 mg/dL should prompt consideration of explanations that include BFHH, renal disease, and the use of thiazide diuretics, among others.
Box 56.1
Diagnostic Workup for Primary Hyperparathyroidism
In a patient found to have hypercalcemia or diagnosed with conditions that can be related to PHPT (osteopenia, osteoporosis, kidney stones)
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Careful history and physical examination, including symptoms, prior head and neck radiation treatments, prior neck surgery, medications, and prior endocrine disorders in the patient and patient’s family
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Initial serum biochemical profile: serum total calcium, serum ionized calcium, intact PTH, serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D
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If this initial profile is compatible with PHPT, complete the diagnostic workup with 24-hour urine collection for measurements of urinary volume, creatinine, and calcium
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Diagnosis is confirmed when there is elevated serum total or ionized calcium or both, in conjunction with elevated or high-normal PTH, and elevated or normal 24-hour urinary calcium
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Note that imaging studies (e.g., ultrasound, 99-Tc sestamibi scan, 4D-computed tomography) are not intended for diagnostic purposes, but as localizing studies obtained after diagnosis and the decision to proceed with surgery
In a patient with normocalcemic hyperparathyroidism (HPT)
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Repeat several serum biochemical profiles. Look for elevation in ionized calcium
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Consider underlying vitamin D deficiency or other causes of secondary HPT and treat appropriately
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Consider calculating the patient’s personal upper limit of normal PTH by the formula PTH [ULN pg/mL] = 120 – (6 × serum calcium mg/dL) – (½ × 25-hydroxyvitamin D ng/mL) + (¼ × patient’s age in years); the measurements of calcium, PTH, and vitamin D should be from the same blood draw; if the patient’s measured serum value of PTH is higher than this calculated ULN PTH, the diagnosis of PHPT would be more likely
In a patient suspected to have other potential causes of hypercalcemia or an initial biochemical profile that shows hypercalcemia with low normal intact PTH, consider screening for
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Bony metastases, sarcoidosis, pulmonary tumors (chest radiograph)
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Multiple myeloma (serum protein electrophoresis)
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PTH-related peptide producing tumors (serum PTHrp)
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Check recent staging for cancer status if history of prior malignancy
In a patient with possible multiple endocrine neoplasia (MEN) type 1 or 2
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Screen for serum or urinary metanephrines before parathyroid surgery
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Complete investigation of endocrinopathies as appropriate for patient’s history
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Genetic testing to confirm MEN 1 or 2 is not required before parathyroidectomy
Although there can be other nonendocrine causes of hypercalcemia coexisting with PHPT, these are exceedingly rare. Separate investigations for these causes is not warranted at the outset in a patient with elevated calcium, intact PTH, and whose medical history does not have pertinent findings (e.g., hypercalcemia-associated malignancies). Such investigations may be helpful in atypical presentations. Obtaining a thorough family history is important to discern possible multiple endocrine neoplasia (MEN), and, if suspected, appropriate additional evaluation can be tailored. Routine genetic testing for MEN 1 (where 90% manifest parathyroid disease) and MEN 2 (where parathyroid disease affects < 5% patients) is unwarranted as part of the initial diagnostic workup for PHPT.
A detail-oriented and meticulous determination of clinical history is essential to enhance recognition of those patients who will be better served with a bilateral exploration. Some investigators have even proposed a scoring system to aid this process, particularly for identifying MEN kindred.
Treatment
Parathyroidectomy has the following operative goals: (1) achieving normocalcemic state and normal long-term PTH, (2) avoiding injury to the laryngeal nerves, (3) engendering minimal postoperative morbidity and negligible mortality, and (4) accomplishing cosmetic scar appearance acceptable to the patient. Surgery remains the most clearly demonstrated mechanism for durable cure of PHPT and symptomatic improvement, particularly related to osteoporosis, bone fractures, and neurocognitive issues. All of the newer surgical techniques that have evolved since the early 2000s share the following goals: focal and unilateral exploration with or without intraoperative PTH measurement, radioguided parathyroid surgery, and videoscopic and robotically assisted parathyroidectomy. It is again important to stress that standard, bilateral parathyroid exploration meets these goals as well; however, some literature has questioned comparative performance with respect to morbidity and cosmetic outcomes. Especially when performed by experienced surgeons, bilateral parathyroid exploration has an excellent long-term track record of curing PHPT and can be achieved with minimal morbidity.
Rationale for Parathyroid Surgery and Bilateral Exploration
Recently-published guidelines for the management of PHPT suggests operative management is clearly indicated for all patients with classic symptoms or complications of PHPT. More challenging has been the perspective of decision making for those patients with apparently asymptomatic PHPT. A combined panel of expert surgeons and endocrinologists issued recently modified guidelines outlining the criteria for surgical referral of patients with asymptomatic PHPT: (1), those patients < 50 years of age; (2), those patients with a serum calcium level > 1.0 mg/dL above the normal range; (3), those patients with T-scores < − 2.5 at lumbar spine, total hip, femoral neck, or distal one-third radius or vertebral fracture on x-ray, computed tomography (CT), magnetic resonance imaging (MRI), or vertebral fracture assessment (VFA); (4), those patients with urinary calcium > 400 mg/24 hour and increased stone risk; and (5), those patients with a creatinine clearance < 60 cc/min.
It is difficult to predict reliably the development, timing, and progression of disease in patients with asymptomatic HPT. Long-term nonoperative management can be costly. For these reasons, other experts have advised a more liberal approach to recommendations of parathyroidectomy beyond the criteria identified by the National Institutes of Health (NIH), provided that surgery can be performed safely and with minimal risks for a disease that, in some patients, may be minimally problematic at the time of presentation.
The indications for bilateral parathyroid exploration as the initial surgery for PHPT, once a patient has met the criteria indicated previously, are listed in Box 56.2 . The guiding principle of bilateral parathyroid exploration is that some patients have significantly higher risk for multigland parathyroid disease. Therefore successfully achieving the operative goal of normocalcemia is contingent upon the evaluation of all parathyroid glands in their usual anatomical locations and upon the appropriate resection of those glands that appear abnormal.
BOX 56.2
Indications for Bilateral Parathyroid Exploration as the Initial Surgery for Parathyroid Disease
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