Review Article
Surgery for Primary Hyperparathyroidism Glenda G. Callender, MD; and Robert Udelsman, MD, MBA
In the Western world, primary hyperparathyroidism is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women. Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging. Primary hyperparathyroidism is a complex disease process that requires careful diagnosis and thoughtful medical and surgical management. The surgical management of patients with persistent or recurrent disease, inherited primary hyperparathyroidism syndromes, and parathyroid carcinoma is particularly challenging. C 2014 American Cancer High-quality imaging and reliable intraoperative adjuncts are critical to success. Cancer 2014;000:000-000. V Society. KEYWORDS: primary hyperparathyroidism, minimally invasive surgery, reopertive parathyroidectomy, parathyroidectomy, parathyroid surgery.
INTRODUCTION Primary hyperparathyroidism (PHPT) was once considered rare and was diagnosed when patients underwent biochemical evaluation because of advanced signs of kidney or bone disease. Development of the multichannel autoanalyzer in the mid-1960s expedited the rapid, inexpensive measurement of serum calcium levels. By the 1970s, most patients were diagnosed because of incidentally discovered hypercalcemia.1 In the Western world, PHPT is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women.2-4 Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging, and surgical treatment requires experience and expertise. Clinical Presentation and Diagnosis
In the United States today, >80% of patients with PHPT are diagnosed because of incidentally discovered hypercalcemia and do not present with the classic symptoms of “stones, bones, moans, groans, and psychiatric overtones.” Nonetheless, the symptoms and signs include nephrolithiasis, osteitis fibrosa cystica, osteoporosis, fractures, bone pain, myopathy, and neuropsychiatric impairment. Approximately 15% to 20% of patients present with nephrolithiasis, and 0.25 mmol/L) above upper limit of normal a. T-score of 2.5 (osteoporosis) b. Vertebral fracture on imaging study a. Reduced below 60 mL/min b. 24 hour urine for calcium > 400 mg/day and increased stone risk by biochemical stone risk analysis c. Nephrolithiasis or nephrocalcinosis on imaging study
Bone mineral density Creatinine clearance
a
Surgery is also indicated in patients who are unwilling or unable to undergo medical surveillance. b Patients need meet only one of these criteria to be advised to have parathyroid surgery.
The most recent guidelines12 recommend that patients with biochemically confirmed PHPT who manifest overt symptoms and signs should undergo surgery. Patients with biochemically confirmed PHPT who lack overt symptoms and signs are considered “asymptomatic.” The current guidelines recommend surgery for “asymptomatic” patients who have measurable markers of disease that is more severe at the outset or more likely to progress: young age (1000 pg/mL), then 6
the resected tissue is not thyroid or lymph node, and there is no need to obtain a frozen section. Parathyroidectomy has become less invasive as novel approaches have been developed in the quest for a cosmetically superior incision. The video-assisted endoscopic technique for parathyroidectomy, which was developed by Miccoli et al, is performed through a 1.5-cm incision in the neck and yields excellent cosmesis.46 Other endoscopic and robotic techniques have used transaxillary, transbreast, and postauricular incisions in an attempt to avoid an incision on the neck.47-51 “Natural orifice” transoral parathyroidectomy requires no skin incision.52 However, it is not clear that the various robotic or endoscopic approaches offer a significant advantage in terms of cosmesis. Parathyroidectomies are routinely performed through a 2.5-cm to 3.5-cm abbreviated Kocher incision placed along existing skin creases; this incision is usually almost invisible once completely healed.53 Robotic and endoscopic approaches also are relatively expensive, timeconsuming, demand sophisticated technology that is not uniformly available and may be associated with increased morbidity.51,54,55 Postoperative management
The patient’s postoperative disposition is determined by the extent of surgery and the risk of hypoparathyroidism. Patients who undergo unilateral neck exploration and meet institutional postanesthesia, same-day discharge criteria may be discharged with prophylactic oral calcium supplementation and instructions about the signs and symptoms of hypocalcemia. Patients who have undergone bilateral neck exploration or reoperative parathyroid surgery may be considered for hospital admission to monitor serum calcium levels, because they are at increased risk of postoperative hypoparathyroidism, although outpatient surgery is often safe. They may require oral or intravenous calcium supplementation (and possibly calcitriol); if admitted to the hospital, serum calcium levels should be stable before discharge. It is critical that accessible telephone contacts are available for the patient, their family, and the surgical team. A postoperative visit with the surgeon is scheduled 1 to 2 weeks after surgery to evaluate wound healing and determine early postoperative cure through measurement of serum calcium and intact PTH levels. Patients with failure of cure (persistent PHPT) should be followed by the surgeon. If reoperation is necessary, then specialized preoperative localization studies may be needed. Surgical cure after parathyroidectomy is defined as normocalcemia 6 months after surgery. Although followCancer
Month 00, 2014
Surgery for Primary Hyperparathyroidism/Callender and Udelsman
Figure 5. Patient positioning is illustrated for minimally invasive parathyroidectomy under regional anesthesia. Reprinted with kind permission of Springer Science & Business Media from Carling and Udelsman, 2012.39
up varies in patients who have undergone parathyroidectomy, it is important to document biochemical cure in all patients. A follow-up visit with the endocrinologist, primary care physician, or surgeon should be scheduled approximately 6 months after surgery to measure serum calcium and intact PTH levels. Patients with failure of cure before 6 months (persistent PHPT) or patients who develop recurrent PHPT after 6 months (recurrent PHPT) should be evaluated for reoperation. The evaluation and management of patients with persistent or recurrent PHPT are discussed below. Outcomes of parathyroid surgery
Parathyroid surgery is safe and effective. Complications include recurrent laryngeal nerve injury, hypoparathyroidism, neck hematoma, pneumothorax, and stroke. Recurrent laryngeal nerve injury occurs in 0.5% to 1% of patients and usually results in hoarseness.53 If nerve injury does not resolve spontaneously, then vocal cord injection or medialization thyroplasty may be necessary. Hypoparathyroidism after parathyroid surgery leads to hypocalcemia. Unilateral neck exploration may result in mild, temporary hypocalcemia, but permanent hypoparathyroidism is rare. Long-term hypoparathyroidism occurs in 0.1% of patients undergoing bilateral neck exploration and is managed with oral calcium and calcitriol supplementation.53 Neck hematoma occurs in 0.2% of patients.53 This is a potential surgical emergency that may require immediate return to the operating room for evacuation and hemostasis. Obtaining and maintaining an adequate airway is of primary importance. If acute airway distress occurs, then the patient may require immediate Cancer
Month 00, 2014
endotracheal intubation, and the incision may be opened at the bedside for decompression. At times, it may be preferable to decompress the hematoma before endotracheal intubation even in the absence of stridor or overt airway compression: venous hypertension can rapidly lead to laryngeal edema and render the airway difficult to observe. An awake, upright, fiberoptic intubation by the most experienced anesthesiologist available may be required. Emergency tracheostomy may be required as a life-saving measure, and the necessary equipment to perform a tracheostomy should be immediately available. Biochemical cure is the expected outcome after parathyroidectomy. However, cure rates depend on the experience of the surgeon and the center. The endocrine community has come to anticipate near-perfect results from parathyroidectomy, because most large studies are reported by high-volume, expert surgeons in centers with high-quality parathyroid imaging and intraoperative adjuncts. Under such circumstances, excellent results are possible. A recent study reporting 1650 consecutive parathyroidectomies demonstrated a cure rate of 99.4% for 1037 patients who underwent MIP and 97.1% for 613 patients who underwent bilateral neck exploration.53 Worldwide, most parathyroid surgery is not performed by a high-volume endocrine surgeon. A study using data from the National Inpatient Sample from 1988 through 2000 reported that only 5% of parathyroidectomies in the United States were performed by a surgeon who had a thyroid, parathyroid, and adrenal case volume that comprised >75% of their practice, and 78% of parathyroidectomies were performed by surgeons who had an endocrine case volume that comprised 25% of their practice.56 Although no American studies have directly compared cure and complication rates between high-volume and low-volume parathyroid surgeons, it is likely that outcomes from low-volume surgeons are not as good. Two studies reported that only 13% to 22% of failures from high-volume centers, but 77% to 89% of operative failures from low-volume centers, were potentially “preventable,” in that the missed parathyroid gland was discovered in a normal, accessible anatomic location at reoperation.57,58 A Scandinavian study used national registry data from 1971 through 1980 to directly compare high-volume and low-volume parathyroid centers: the cure rate in endocrine surgery centers was 90% versus 76% in general surgery clinics and only 70% in centers that performed
Surgery for Primary Hyperparathyroidism Glenda G. Callender, MD; and Robert Udelsman, MD, MBA
In the Western world, primary hyperparathyroidism is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women. Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging. Primary hyperparathyroidism is a complex disease process that requires careful diagnosis and thoughtful medical and surgical management. The surgical management of patients with persistent or recurrent disease, inherited primary hyperparathyroidism syndromes, and parathyroid carcinoma is particularly challenging. C 2014 American Cancer High-quality imaging and reliable intraoperative adjuncts are critical to success. Cancer 2014;000:000-000. V Society. KEYWORDS: primary hyperparathyroidism, minimally invasive surgery, reopertive parathyroidectomy, parathyroidectomy, parathyroid surgery.
INTRODUCTION Primary hyperparathyroidism (PHPT) was once considered rare and was diagnosed when patients underwent biochemical evaluation because of advanced signs of kidney or bone disease. Development of the multichannel autoanalyzer in the mid-1960s expedited the rapid, inexpensive measurement of serum calcium levels. By the 1970s, most patients were diagnosed because of incidentally discovered hypercalcemia.1 In the Western world, PHPT is now a relatively common disorder that is diagnosed in 0.7% of the general population and in 2% of postmenopausal women.2-4 Although patients today typically present with less severe manifestations of disease, the evaluation and management of patients with parathyroid disease remains challenging, and surgical treatment requires experience and expertise. Clinical Presentation and Diagnosis
In the United States today, >80% of patients with PHPT are diagnosed because of incidentally discovered hypercalcemia and do not present with the classic symptoms of “stones, bones, moans, groans, and psychiatric overtones.” Nonetheless, the symptoms and signs include nephrolithiasis, osteitis fibrosa cystica, osteoporosis, fractures, bone pain, myopathy, and neuropsychiatric impairment. Approximately 15% to 20% of patients present with nephrolithiasis, and 0.25 mmol/L) above upper limit of normal a. T-score of 2.5 (osteoporosis) b. Vertebral fracture on imaging study a. Reduced below 60 mL/min b. 24 hour urine for calcium > 400 mg/day and increased stone risk by biochemical stone risk analysis c. Nephrolithiasis or nephrocalcinosis on imaging study
Bone mineral density Creatinine clearance
a
Surgery is also indicated in patients who are unwilling or unable to undergo medical surveillance. b Patients need meet only one of these criteria to be advised to have parathyroid surgery.
The most recent guidelines12 recommend that patients with biochemically confirmed PHPT who manifest overt symptoms and signs should undergo surgery. Patients with biochemically confirmed PHPT who lack overt symptoms and signs are considered “asymptomatic.” The current guidelines recommend surgery for “asymptomatic” patients who have measurable markers of disease that is more severe at the outset or more likely to progress: young age (1000 pg/mL), then 6
the resected tissue is not thyroid or lymph node, and there is no need to obtain a frozen section. Parathyroidectomy has become less invasive as novel approaches have been developed in the quest for a cosmetically superior incision. The video-assisted endoscopic technique for parathyroidectomy, which was developed by Miccoli et al, is performed through a 1.5-cm incision in the neck and yields excellent cosmesis.46 Other endoscopic and robotic techniques have used transaxillary, transbreast, and postauricular incisions in an attempt to avoid an incision on the neck.47-51 “Natural orifice” transoral parathyroidectomy requires no skin incision.52 However, it is not clear that the various robotic or endoscopic approaches offer a significant advantage in terms of cosmesis. Parathyroidectomies are routinely performed through a 2.5-cm to 3.5-cm abbreviated Kocher incision placed along existing skin creases; this incision is usually almost invisible once completely healed.53 Robotic and endoscopic approaches also are relatively expensive, timeconsuming, demand sophisticated technology that is not uniformly available and may be associated with increased morbidity.51,54,55 Postoperative management
The patient’s postoperative disposition is determined by the extent of surgery and the risk of hypoparathyroidism. Patients who undergo unilateral neck exploration and meet institutional postanesthesia, same-day discharge criteria may be discharged with prophylactic oral calcium supplementation and instructions about the signs and symptoms of hypocalcemia. Patients who have undergone bilateral neck exploration or reoperative parathyroid surgery may be considered for hospital admission to monitor serum calcium levels, because they are at increased risk of postoperative hypoparathyroidism, although outpatient surgery is often safe. They may require oral or intravenous calcium supplementation (and possibly calcitriol); if admitted to the hospital, serum calcium levels should be stable before discharge. It is critical that accessible telephone contacts are available for the patient, their family, and the surgical team. A postoperative visit with the surgeon is scheduled 1 to 2 weeks after surgery to evaluate wound healing and determine early postoperative cure through measurement of serum calcium and intact PTH levels. Patients with failure of cure (persistent PHPT) should be followed by the surgeon. If reoperation is necessary, then specialized preoperative localization studies may be needed. Surgical cure after parathyroidectomy is defined as normocalcemia 6 months after surgery. Although followCancer
Month 00, 2014
Surgery for Primary Hyperparathyroidism/Callender and Udelsman
Figure 5. Patient positioning is illustrated for minimally invasive parathyroidectomy under regional anesthesia. Reprinted with kind permission of Springer Science & Business Media from Carling and Udelsman, 2012.39
up varies in patients who have undergone parathyroidectomy, it is important to document biochemical cure in all patients. A follow-up visit with the endocrinologist, primary care physician, or surgeon should be scheduled approximately 6 months after surgery to measure serum calcium and intact PTH levels. Patients with failure of cure before 6 months (persistent PHPT) or patients who develop recurrent PHPT after 6 months (recurrent PHPT) should be evaluated for reoperation. The evaluation and management of patients with persistent or recurrent PHPT are discussed below. Outcomes of parathyroid surgery
Parathyroid surgery is safe and effective. Complications include recurrent laryngeal nerve injury, hypoparathyroidism, neck hematoma, pneumothorax, and stroke. Recurrent laryngeal nerve injury occurs in 0.5% to 1% of patients and usually results in hoarseness.53 If nerve injury does not resolve spontaneously, then vocal cord injection or medialization thyroplasty may be necessary. Hypoparathyroidism after parathyroid surgery leads to hypocalcemia. Unilateral neck exploration may result in mild, temporary hypocalcemia, but permanent hypoparathyroidism is rare. Long-term hypoparathyroidism occurs in 0.1% of patients undergoing bilateral neck exploration and is managed with oral calcium and calcitriol supplementation.53 Neck hematoma occurs in 0.2% of patients.53 This is a potential surgical emergency that may require immediate return to the operating room for evacuation and hemostasis. Obtaining and maintaining an adequate airway is of primary importance. If acute airway distress occurs, then the patient may require immediate Cancer
Month 00, 2014
endotracheal intubation, and the incision may be opened at the bedside for decompression. At times, it may be preferable to decompress the hematoma before endotracheal intubation even in the absence of stridor or overt airway compression: venous hypertension can rapidly lead to laryngeal edema and render the airway difficult to observe. An awake, upright, fiberoptic intubation by the most experienced anesthesiologist available may be required. Emergency tracheostomy may be required as a life-saving measure, and the necessary equipment to perform a tracheostomy should be immediately available. Biochemical cure is the expected outcome after parathyroidectomy. However, cure rates depend on the experience of the surgeon and the center. The endocrine community has come to anticipate near-perfect results from parathyroidectomy, because most large studies are reported by high-volume, expert surgeons in centers with high-quality parathyroid imaging and intraoperative adjuncts. Under such circumstances, excellent results are possible. A recent study reporting 1650 consecutive parathyroidectomies demonstrated a cure rate of 99.4% for 1037 patients who underwent MIP and 97.1% for 613 patients who underwent bilateral neck exploration.53 Worldwide, most parathyroid surgery is not performed by a high-volume endocrine surgeon. A study using data from the National Inpatient Sample from 1988 through 2000 reported that only 5% of parathyroidectomies in the United States were performed by a surgeon who had a thyroid, parathyroid, and adrenal case volume that comprised >75% of their practice, and 78% of parathyroidectomies were performed by surgeons who had an endocrine case volume that comprised 25% of their practice.56 Although no American studies have directly compared cure and complication rates between high-volume and low-volume parathyroid surgeons, it is likely that outcomes from low-volume surgeons are not as good. Two studies reported that only 13% to 22% of failures from high-volume centers, but 77% to 89% of operative failures from low-volume centers, were potentially “preventable,” in that the missed parathyroid gland was discovered in a normal, accessible anatomic location at reoperation.57,58 A Scandinavian study used national registry data from 1971 through 1980 to directly compare high-volume and low-volume parathyroid centers: the cure rate in endocrine surgery centers was 90% versus 76% in general surgery clinics and only 70% in centers that performed
