James T. Broome
Presentation
A 57-year-old man with a history of peptic ulcer disease is referred for management of persistent hypercalcemia. He initially presented to his primary care physician for routine physical examination where a basic metabolic panel revealed serum calcium elevated at 12.1 mg/dL. Subsequent workup demonstrated an ionized calcium of 6.61 mg/dL (normal, 4.48 to 5.28), serum calcium of 12.4 mg/dL (normal, 8.5 to 10.5), parathyroid hormone (PTH) level of 248 pg/dL (normal, 10 to 65), and a total 25 OH vitamin D level of 39 ng/mL (normal, 30 to 80). Preoperative sestamibi documented a right-sided abnormality (Figure 1). However, ultrasound was not done. He went to the operating room 6 months prior to presentation for exploration. During surgery, he underwent exploration and subsequent partial right thyroid lobectomy after failure to identify a parathyroid adenoma. Postoperatively, he has remained hypercalcemic prompting referral for persistent hyperparathyroidism.
FIGURE 1 • Tc-99 Sestamibi documenting persistent uptake in right cervical position.
Differential Diagnosis
Primary hyperparathyroidism is by far the most common cause of hypercalcemia. Other less common causes include malignancy, granulomatous disease(s), milk-alkali syndrome, and many others. Hypercalcemia with concurrent hyperparathyroidism (elevated PTH levels) has a much narrower differential diagnosis including sporadic primary hyperparathyroidism, familial isolated hyperparathyroidism, multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 2a (MEN 2a), medication-induced (lithium, HCTZ), secondary hyperparathyroidism (end-stage renal disease, hypovitaminosis D), and familial hypocalciuric hypercalcemia (FHH). In the patient in whom initial surgery for presumed primary hyperparathyroidism has failed to produce biochemical cure, a systematic approach must be undertaken to verify the diagnosis and indications for further intervention(s).
Workup
The patient undergoes further workup to delineate the cause of his hyperparathyroidism. Repeat serum calcium and PTH levels are 11.9 mg/dL and 225 pg/dL, respectively. Ionized calcium is elevated at 6.3 mg/dL, renal function is normal, and his total 25 OH vitamin D level is normal at 40 ng/mL. The patient is not taking any confounding/contributing medications and denies any known family history of calcium disorders. A 24-hour urine collection for calcium demonstrates his urine calcium to be 239 mg of calcium in 24 hours (normal, 100 to 300 mg/24 h) which rules out FHH. Based on this workup, he continues to have a picture consistent with primary hyperparathyroidism.
The pathology report documents removal of an inferior parathyroid gland attached to the outer surface of the right thyroid lobe. The operative note describes identification of the right recurrent laryngeal nerve from its appearance under the subclavian artery up to its insertion into the cricopharyngeal joint. No visual confirmation was reported of the right superior gland, and the right inferior gland was removed at the time of thyroid lobectomy. There was no mention of exploration of the carotid sheath, removal of the cervical thymus, or exploration of the tracheoesophageal groove. The surgeon did not explore the left side of the neck during the first operation.
Although preoperative localization may be bypassed at initial operation, successful reoperative parathyroid surgery demands an exhaustive search for the pathologic gland. Ideally, two concordant localization studies should be obtained prior to proceeding with reexploration. Routine ultrasonography should be performed for all reoperative parathyroid patients. Ultrasound not only evaluates for the typical perithyroidal cervical adenomas but can also detect intrathyroidal lesions that may represent intrathyroidal parathyroid adenomas or thyroid nodular disease necessitating concurrent treatment at the time of reoperation. A detailed ultrasound should also include evaluation of both carotid sheaths from above the bifurcation of the common carotid artery down to the anterior mediastinum as allowed by body habitus. Fine needle aspiration of suspicious lesions can be sent for PTH washings/measurements to confirm parathyroid tissue prior to surgery. Ultrasound is not a good imaging test for identifying mediastinal lesions or those ectopic adenomas located posterior to the larynx, trachea, or esophagus.
Routine imaging should also include repeat technetium-99 Sestamibi scanning, preferable with single photon emission computed tomography (SPECT) for added anatomic detail. The sensitivity of sestamibi is decreased in reoperative surgery, but it has the advantage of evaluating deep structures in the neck (retrotracheal, retrolaryngeal) as well as identifying potential mediastinal adenomas.
High-resolution computed tomography (CT) scanning, either with computed tomography angiography (CTA) or 4D-CT, plays an important role in localization of missing glands. Adenomas will typically “light up” on arterial-phase imaging, and these modalities have essentially replaced percutaneous angiography for parathyroid localization. Accurate CT scan interpretation demands familiarity with the cervical anatomy and knowledge of the common locations for missing adenomas. Thin slice (2 to 3 mm) scans provide detailed examination of the carotid sheath, retrotracheal, retroesophageal, and mediastinal locations of adenomas. Institutional preferences and protocols should be considered when deciding between CTA versus 4D-CT scans. Other potential imaging utilizing MRI or C11 Methionine PET/CT for localization may be considered if other modalities have failed to demonstrate a missing adenoma.
Selective venous sampling (SVS) of the cervical and thoracic venous system provides another potential technique for localization. This demands a high level of technical skill from the interventional radiologist. SVS consists of multiple detailed measurements of PTH values from various locations within the cervical–thoracic venous system. Subsequent diagrams of the venous system mapped with the corresponding PTH values help to determine laterality to the parathyroid adenoma as well as demonstrate evidence of mediastinal drainage. Detailed anatomic information is difficult to extrapolate from SVS data.
Diagnosis and Treatment
The diagnosis of primary hyperparathyroidism can be difficult to make in some patients, and accuracy is of vital importance in the case of persistent hyperparathyroidism. A thorough understanding of the relationship of serum calcium to PTH levels can help the clinician look for common errors in diagnosis and confirm the etiology of the hypercalcemia. A detailed clinical history should be able to rule out specific disorders related to ingestion of supraphysiologic doses of supplements containing calcium, vitamin D, or excessive dietary intake of calcium and vitamin D foods. Specific attention must be paid to the family history in an attempt to screen for underlying genetic disorders related to calcium homeostasis. A strong family history of calcium disorders may suggest an undiagnosed MEN syndrome, FHH, or familial isolated hyperparathyroidism. Young patients (<30 years old) with hypercalcemia should raise suspicion of an unrecognized familial form of hyperparathyroidism. The diagnosis rests upon accurate measurements of concurrent serum calcium, ionized calcium, albumin, and PTH levels.
Once primary hyperparathyroidism is confirmed biochemically, the surgeon must next reexamine the indications for surgical intervention. Reoperative parathyroid surgery carries increased risk of injury to the recurrent laryngeal nerve, permanent hypoparathyroidism, as well as an increased rate of failure to cure the hyperparathyroidism. Before undertaking these risks, careful delineation of the indication for surgery must be outlined. The indications for reoperative surgery are no different than those for an initial exploration and generally follow the National Institute of Health guidelines. Laboratory and radiologic evidence of end-organ damage related to the hyperparathyroidism must be documented. All symptomatic patients with osteoporosis, osteofibrosis cystica, Brown’s tumors, kidney stones, or life-threatening episodes of hypercalcemia should undergo operation. The “asymptomatic” patients with severe hypercalcemia (>1 mg/dL above normal), hypercalcuria (>400 mg/24 h), osteoporosis (T-score less than -2.5 at any site), prior low-impact fracture, decreased kidney function (creatinine clearance <60 mL/min), or age <50 years should also be considered for reoperation.
Surgical Approach
Prior to any reoperative neck surgery, flexible laryngoscopy should be performed preoperatively to document vocal cord dysfunction from unrecognized recurrent laryngeal nerve injury.
As with any reoperative surgery, a thorough understanding of what has been done before is essential. Prior operative reports should be obtained and carefully reviewed. Particular attention should be paid to key structures visualized during the first operation (e.g., were the recurrent nerves identified? was any thyroid arterial supply ligated and where?). Visual identification of parathyroids and their location, even by trusted surgeons, should be viewed with skepticism. Even the most experienced surgeon can incorrectly identify a parathyroid gland intraoperatively. Pathologic confirmation of identified glands either by biopsy, excision, or aspiration for PTH levels is needed to feel confident the glands were correctly identified during prior surgery. The surgeon must also note which glands have been removed and anticipate what functional glands may remain, keeping in mind that biopsy of glands at previous exploration may have rendered them nonfunctional. Once the surgeon has convincing evidence suggesting a location for the missing adenoma, surgical approach can be determined (Table 1). A standard anterior approach the central neck is commonly used and has the advantage of familiarity for most surgeons. Scar from prior surgery and loss of normal tissue planes increase potential complications as well as limiting the success of “blind” exploration. A standard collar (Kocher) incision should be made roughly overlying the isthmus of the thyroid gland. Full mobilization of the strap muscles from their origin to insertion allows generous access to the central neck. If the lesion has been accurately localized or lateralized preoperatively, then a lateral approach to the central neck may provide an alternative exposure that avoids previously disrupted tissue planes and minimizes the impact of prior surgical scarring. This approach involves separating the medial border of the sternocleidomastoid muscle from the lateral border of the strap muscles allowing access to the central neck while also avoiding the scarring present along the midline. From this approach, the surgeon can access the inferior thyroidal artery, accurately identify and preserve the recurrent laryngeal nerve, as well as allow exposure of the carotid sheath and tracheoesophageal groove. Regardless of the approach used, a suspected parathyroid(s) should be sent for frozen section to confirm an accurate pathologic diagnosis and prevent misidentification. Intraoperative PTH monitoring should also be utilized to confirm removal of all hyperactive parathyroid tissue. Failure of PTH levels to drop >50% 10 minutes after removal of the gland should prompt further central neck exploration for another hyperactive gland when feasible.
TABLE 1. Key Technical Steps and Potential Pitfalls to Reoperative Parathyroidectomy
The surgeon must also be familiar with the common and uncommon locations of “missing” parathyroid glands. Knowledge of the embryologic formation and descent of the parathyroids will aid in an educated search for missing glands. The most common location for a “missing” parathyroid adenoma is routine/regular anatomic locations. Inferior parathyroid glands are typically located within a 2-cm2 area around the inferior pole of the thyroid gland. Superior glands are also typically located within 2 cm superior to the recurrent laryngeal nerve as it crosses the inferior thyroidal artery. The most common ectopic location of missing inferior adenomas is the cervical thymus. Inferior glands may also be located within the ipsilateral thyroid lobe, carotid sheath, or anterior mediastinum. Median sternotomy is inappropriate during a search for a missing adenoma unless preoperative imaging demonstrated a mediastinal location. Superior glands may be located high along the path of the superior thyroid pedicle, deep along the prevertebral fascia, as well as within the tracheoesophageal groove. Mobilization of the trachea and esophagus will allow evaluation for retrolaryngeal or retroesophageal glands. Often, enlarged superior glands “descend” behind the inferior thyroidal artery and recurrent laryngeal nerve to lie inferior to these structures within the tracheoesophageal groove.
In this case, after surgeon’s review of the prior operative note, pathology report, localization studies and biochemical confirmation of primary hyperparathyroidism, the patient underwent repeat sestamibi scanning and ultrasonography. Surgeon-performed ultrasound demonstrated a diminutive right thyroid lobe, no intrathyroidal lesions within the right or left thyroid lobes, as well as no suspicious/hypoechoic lesions in the bilateral central neck or within the carotid sheaths bilaterally. Sestamibi/SPECT was consistent with a left superior abnormality located just behind the superior pole of the left thyroid lobe (Figure 2). CTA of the neck and mediastinum was then performed, demonstrating a hypervascular mass located in a retrolaryngeal position next to the left superior thyroid lobe (Figures 3 and 4). There was no evidence of a mediastinal adenoma on either sestamibi or CTA. Decision was made to take him to the operating room for PTH-guided parathyroidectomy of a suspected left superior parathyroid gland.
FIGURE 2 • Fused sestamibi-SPECT axial images—arrows demonstrate left superior adenoma.
FIGURE 3 • Axial CTA images—white arrow indicates leftsided parathyroid adenoma.
FIGURE 4 • Sagittal CTA images—white arrow indicates posterior location of left superior adenoma.
Special Intraoperative Considerations
Several scenarios must be considered intraoperatively even in those patients in whom a single adenoma is suspected by history and localization studies. Multiglandular disease (MGD), either from sporadic hyperplasia or a familial syndrome, may still be present. In those patients in whom MGD is confirmed, the surgeon should proceed with complete cervical exploration, excision of parathyroid tissue, and reimplantation of approximately 30 to 40 mg of morselized parathyroid tissue into the nondominant brachioradialis muscle. Individual surgeon experience and preference ultimately determine between autotransplantation versus creation of an appropriate in situ parathyroid remnant. Cryopreservation of residual parathyroid tissue should be performed if available at the institution. Bilateral exploration may not be possible due to intense scarring and consideration should be given to the use of intraoperative recurrent laryngeal nerve monitoring in these difficult cases.
The surgeon must also be prepared to encounter parathyromatosis. In this situation, abnormal parathyroid tissue released during a prior exploration has implanted into surrounding contiguous structures leading to diffuse seeding of hyperactive parathyroid tissue. Although difficult to achieve permanent normocalcemia, the surgeon should be prepared to perform a complete excision of all identifiable parathyroid implants including resection of involved strap muscles, thyroid lobe, as well as ipsilateral central lymph node dissection.
Finally, consideration must be given to the potential that resection of an adenoma will result in removal of all remaining functional parathyroid tissue. This scenario can be anticipated after detailed review of prior operative notes and pathology reports. If suspected, then utilization of PTH monitoring may demonstrate a precipitous drop in PTH levels confirming the absence of residual functional tissue. The surgeon must save a portion of the histologically confirmed hypercellular parathyroid for morselization and reimplantation. If PTH levels remain detectable but suspicion of hypoparathyroid is high, then cryopreservation of parathyroid tissue for possible reimplantation later should be performed.
Postoperative Management
Reoperative patients should be brought back to clinic in 1 to 2 weeks for postoperative evaluation for hypocalcemia, wound healing, vocal strength, as well as resolution of any symptoms present preoperatively. Serum calcium and PTH levels should be checked to document biochemical normalization of the PTH-calcium axis. Calcium and PTH levels should be rechecked at 6 months postoperatively to confirm persistent resolution of hyperparathyroidism. Calcium alone may be checked yearly thereafter to monitor for long-term recurrence, which should be <5% after 10 years. Hypoparathyroidism with hypocalcemia can be treated surgically with reimplantation of cryo-preserved parathyroid tissue if available or medically with oral calcium supplements and activated 1,25 OH vitamin D. Those patients with insufficient or deficient 25 OH vitamin D levels should receive a course of ergocalciferol for supplementation in addition to calcium and 1,25 OH vitamin D.
Case Conclusion
The patient was taken to the operating room where he underwent a lateral approach the left central neck. Exploration of the space just posterior the left superior pole demonstrated a large, 2.1-cm left superior parathyroid adenoma. The gland weight 1.34 g. Intraoperative PTH levels dropped from 530 pg/mL down to 87 pg/mL 10 minutes after division of the single vascular pedicle to the adenoma. The patient was discharged home the same day after a brief period of observation in the postanesthesia care unit.
The patient’s repeat serum calcium at 2 weeks postoperatively was 9.4 mg/dL with a concurrent PTH of 24 pg/mL. There was no clinical evidence of hypocalcemia or vocal cord paresis/paralysis. He described marked improvement in energy levels, mood, and resolution of esophageal reflux symptoms. At 6 months, the patient remained normocalcemic with serum calcium of 9.3 mg/dL.
TAKE HOME POINTS
· Biochemical reconfirmation of the diagnosis of hyperparathyroidism along with consideration of familial/genetic etiology should be conducted.
· Reoperative central neck surgery carries two to three times higher than baseline risk of complications including recurrent laryngeal nerve paralysis and permanent hypoparathyroidism.
· The surgeon must review of prior operative reports, pathology reports, localization studies and have a thorough understanding of parathyroid embryology and anatomy.
· Preoperative localization should involve at least two concordant imaging studies progressing from noninvasive to more invasive studies as necessary. At least one study should give anatomical detail.
· Most “missing” adenomas are found in standard locations around the thyroid gland.
· Reoperative surgery should be performed by a surgeon who is experienced in parathyroid surgery and reoperative cervical explorations.
SUGGESTED READINGS
Henry JF. Reoperation for primary hyperparathyroidism: tips and tricks. Langenbecks Arch Surg. 2010;395:103–109.
Powell AC, Alexander R, Chang R, et al. Reoperation for parathyroid adenoma: a contemporary experience. Surgery. 2009;146:1144–1155.
Richards ML, Thompson GB, Farley DR, et al. Reoperative parathyroidectomy in 228 patients during the era of minimal-access surgery and intraoperative parathyroid hormone monitoring. Am J Surg. 2008;196:937–943.