For those surgeons who prefer the unilateral approach and use IOPTH, exploration begins on the side suggestive of the adenoma on imaging (typically ultrasound or sestamibi scanning). Figure 20.1 is a flow diagram demonstrating decision making for those who may be candidates for unilateral exploration. If only one abnormal gland is identified and the intraoperative PTH drops to an appropriate level, then the operation is terminated. Some surgeons examine the ipsilateral gland in order to evaluate for multigland disease. If an additional enlarged gland is identified and/or the PTH value remains inappropriately elevated, then the remaining parathyroid glands on the contralateral side are explored. Once a diagnosis multigland disease is established, the remaining parathyroid glands should be identified but not yet resected. If four-gland hyperplasia is present and three-and-a-half-gland parathyroidectomy (subtotal parathyroidectomy) is carried out, the most abnormal/enlarged glands should be resected first, leaving a 50-100 mg remnant. The remnant should be marked with a stitch or clip as these patients may have germline defects driving parathyroid proliferation and will be at risk for recurrence.

In rare instances, imaging will suggest multigland involvement in pHPT. These patients are not candidates for the unilateral approach and should undergo bilateral exploration and four-gland examination. Multigland disease is thought to occur in 10–20 % of patients with pHPT [5, 6]. In any suspected case of multigland disease, all parathyroid glands should be exposed and examined with an intraoperative determination of extent of parathyroidectomy. However, it is rare to identify mutligland disease on preoperative imaging. A consistent finding among multigland pHPT patients is nonlocalizing preoperative imaging [7]. The reasons for this are unclear but may be related to gland size in multigland disease. Any patient with subtle multigland findings or nonlocalizing findings on imaging should be considered for bilateral exploration. Intraoperative PTH testing can still serve as an adjunct to visual inspection and can help determine extent of resection.

Patients with germline mutations in the MENIN (MEN1) or RET gene (MEN2A) are at high risk for pHPT and multigland disease. Indications for surgery are similar to that of nonfamilial disease. However, familial patients are at much higher risk of developing recurrent disease since they have a germline driver of parathyroid growth. Thus, all parathyroid cells in these patients can be considered abnormal. This is demonstrated by H + E staining of parathyroid glands from patients with adenomas versus those with hyperplasia (i.e. multigland disease) (Fig. 20.2). Parathyroid adenomas occur as a single focus of neoplasia, associated with somatic mutation events. This can be seen histologically as the hypercellular adenoma abutting normal parathyroid tissue. In contrast, hyperplastic glands, or those associated with familial syndromes, have changes throughout the gland with noted nodularity of hyperplastic cells and an absence of normal gland architecture.

MEN1 is a common cause of familial hyperparathyroidism. The most common initial presentation of these patients is hypercalcemia and elevated PTH levels [8]. Although a family history of parathyroid disease is commonly discovered at the initial clinic visit, in some cases the parathyroid surgeon may not be not be aware of the patient’s familial syndrome prior to operation. Any patient found to have multigland pHPT should be considered for MENI and medical genetics referral. The surgical approach to these patients includes bilateral exploration, identification of all four parathyroid glands and a cervical thymectomy in case of an ectopic or supernumerary parathyroid gland located in the thymus. It should be noted that ectopic/supernumerary rests of parathyroid tissue are relatively common given the embryology of parathyroid glands (discussed below) and in familial cases this tissue can be a source of persistent or recurrent disease after exploration. Subtotal parathyroidectomy (or three-and-a-half-gland parathyroidectomy) has been advocated over total parathyroidectomy with forearm autograft for these patients to reduce the severity of postoperative hypoparathyroidism and hypocalcemia [9]. Notably, familial patients are at risk of recurrent pHPT given their germline mutations. If a patient has undergone a subtotal parathyroidectomy and has recurrent disease/symptoms, the second operation can have additional challenges. First, these patients are undergoing redo neck surgery, which can lower rates of success depending on the degree of scar tissue. Second, partial resection of a parathyroid remnant with an unpredictable blood supply can place the new parathyroid remnant at risk. For these reasons some surgeons prefer to perform cryopreservation of parathyroid tissue in case of postoperative hypoparathyroidism. We generally take a conservative approach to initial parathyroidectomy in MEN1 patients and operate when symptoms and hypercalcemia absolutely require intervention.

MEN2A patients (mutations in the RET gene) also manifest hyperparathyroidism. However, these patients are also at risk for medullary thyroid carcinoma, which generally guides timing of thyroidectomy and neck exploration. Because total thyroidectomy can affect parathyroid blood supply and the phenotype of hyperparathyroidism is thought to be less severe in MEN2A, a more conservative approach to parathyroidectomy can be employed [10]. Different RET mutations in MEN2A carry different recommendations for timing of prophylactic thyroidectomy. When young children and infants with MEN2A undergo thyroidectomy, special consideration must be given to the parathyroids and these operations are often performed in relatively high volume centers. Recent experience suggests a conservative approach to parathyroidectomy during prophylactic thyroidectomy is warranted [11].

In some cases, the initial parathyroid operation fails to reduce PTH and calcium levels. Persistent pHPT is distinguished from recurrent pHPT by elevated calcium levels less than 6 months after neck exploration. To avoid permanent hypoparathyroidism, a thorough review of the patient’s course should be undertaken. Prior to repeat neck exploration, the previous operative reports and imaging studies should be studied in detail. Pathology of all removed tissue should be reviewed. Patients in this setting are at higher risk of permanent hypoparathyroidism since previous operations likely removed parathyroid tissue. Every attempt should be made to preserve normal parathyroids in the reoperative setting. A bilateral approach is appropriate to carefully identify all remaining parathyroids followed by an appropriate resection (subtotal for hyperplasia, resection of a single adenoma). Intraoperative PTH can also assist with extent of resection. Repeat neck operations can result in high morbidity (cranial nerve injury, bleeding, and hypoparathyrodism) and for this reason some surgeons will repeat localization studies or perform 4D CT in an attempt to localize abnormal parathyroid glands [12].