Even in the most skilled of hands, a small percentage of patients will not be cured after reoperative parathyroid surgery. Reoperative parathyroid surgery can be dangerous even for the most experienced surgeons and is associated with higher complication rates. Damage to the recurrent laryngeal nerve (RLN) , hypoparathyroidism, and persistent hyperparathyroidism are the common complications associated with reoperative parathyroid surgery [1]. Reoperative parathyroid surgery is often indicated for persistent primary hyperparathyroidism and recurrent primary hyperparathyroidism. Persistent primary hyperparathyroidism is defined as a failure of serum calcium and parathyroid hormone (PTH) normalization after a parathyroidectomy operation. Recurrent primary hyperparathyroidism occurs when serum calcium and PTH levels are initially normal but become elevated 6 months after surgery [2]. This is common in patients who have undergone a subtotal parathyroidectomy without correction of the underlying abnormality, such as renal disease. This represents a separate entity and will not be considered an unsuccessful operation.

Unsuccessful reoperative parathyroid surgery can result from the misdiagnosis of hyperparathyroidism , the failure to identify affected parathyroid glands radiographically or surgically, incomplete or inappropriate use/interpretation of intraoperative PTH measurements, and lack of adequate postsurgical follow-up. Lack of surgical experience and surgery performed at low-volume surgical centers have shown to have increased rates of unsuccessful repeat surgery [3]. This chapter aims to review common causes of reoperative parathyroid surgery failure with hopes to improve surgical outcomes in this difficult patient population.

Obtaining the correct diagnosis of primary hyperparathyroidism is crucial to successful reoperative parathyroid surgery. Given the increased morbidity associated with re-exploration, the threshold for surgery in remedial operations should be more stringent than for patients undergoing primary surgery. Several diagnoses must be ruled out prior to proceeding with repeat surgery to avoid poor surgical outcomes. Endocrine disorders can mimic primary hyperthyroidism, and a careful preoperative workup is necessary to prevent unsuccessful reoperations or unnecessary operations. In one study, 144 patients who had had previous parathyroid surgery requiring reoperation were evaluated with hopes of improving success rates in parathyroid reoperations. Successful reoperation was defined by prolonged reversal of hypercalcemia. The most common cause of recurrent hyperparathyroidism in their cohort was multiple endocrine neoplasia type 1 (MEN1) . Failure of adequate preoperative family history can lead to the failed diagnosis of this disorder, resulting in persistent or recurrent hyperparathyroidism. MEN1 is associated with multiglandular, ectopic, and supernumerary disease. The presence of the syndrome is often not evident at the time of primary operation but can be revealed in prolonged follow-up [4]. The optimal surgical treatment for MEN1 is frequently under debate, but typically involves either total or subtotal parathyroidectomy. Persistent hyperparathyroidism is more frequent after subtotal parathyroidectomy than after total parathyroidectomy with autologous graft of parathyroid tissue. Recurrent hyperparathyroidism has a similar frequency in the two surgical strategies. Genetic testing should be performed on all young patients diagnosed with hyperparathyroidism [5]. In one study, outcomes for 130 consecutive remedial parathyroid explorations were reviewed, resulting in seven failed reoperations due to persistent disease . Four of these patients had multi-gland hyperplasia, one was diagnosed with multiple endocrine neoplasia type 2A (MEN 2A) , and one had an occult supernumerary gland after four gland excisions [6].

Not only can unsuccessful parathyroid surgery be secondary to misdiagnosis of primary hyperparathyroidism, certain diseases can mimic normocalcemia in postoperative patients leading to the false belief that the patient has been cured. Similarly, a surgical cure can be incorrectly considered unsuccessful and lead to unnecessary reoperations if not monitored closely. When using surgical adjuncts such as intraoperative PTH (ioPTH) assays as criteria for intraoperative success, it is important to be aware of factors that can falsely alter the measurement. For example, in one large study, younger patients were found to have lower preoperative serum calcium, PTH levels, and ioPTH levels than older patients [7]. Metabolic disorders and poor renal function may falsely elevate the ioPTH. Vitamin D is a known inhibitor of PTH secretion and cause of secondary hyperparathyroidism. These patients may experience deceptive normocalcemia and elevated PTH after parathyroidectomy and have also been shown to have larger adenoma size [8]. These findings may play a role in failure of reoperative parathyroid surgery and support postoperative Vitamin D supplementation in this population [7, 9, 10].

Failure to formulate a well-rounded differential diagnosis and accurately diagnose causes of hypercalcemia and/or hyperparathyroidism can lead to poor outcomes and failure of repeat surgical operations for this population of patients. The differential diagnosis includes hypercalcemia of malignancy, which can falsely elevate calcium and PTH levels. Measurement of an intact PTH (iPTH) level can aid in the differentiation of these diseases; iPTH is generally low in hypercalcemia of malignancy. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder that is imperative to diagnose correctly as parathyroidectomy is not indicated for this disorder. An abnormal calcium-sensing receptor characterizes this disease, leading to hypercalcemia, normal or high PTH, and low urinary calcium excretion. The calcium/creatinine clearance is typically <0.01 in FHH [11]. Other important causes of hypercalcemia that the surgeon should be familiar with include exogenous calcium, medications (thiazides and lithium), granulomatous diseases, and metabolic diseases [12].

Numerous studies have emphasized the need for accurate imaging prior to considering parathyroid surgery. The intraoperative features used to identify parathyroid adenomas such as color, shape, and tactile perception of gland may be much more difficult to appreciate because of fibrosis within the tissues from the previous procedure. For these reasons, most surgeons agree that preoperative imaging studies are an essential component of the workup prior to reoperative parathyroid surgery [13]. Preoperative localization can reduce complication rates and shorten operating time by directing the surgeon to the sites of abnormal glands. The lack of appropriate diagnosis radiographically can lead to unsuccessful reoperative parathyroid surgery.

Recent advances in preoperative localization have led to substantial improved outcomes after remedial surgery. Chen et al. evaluated 254 patients with hyperparathyroidism and found that the positive predictive values for sestamibi scanning, radioguided surgery, and ioPTH testing were 81%, 88%, and 99.5%, respectively [14]. Yen et al. proposed that ultrasonography and sestamibi scans should be performed before all reoperative parathyroid operations [15]. Shen et al. found that the sensitivities of preoperative localization studies were as follows: technetium Tc 99m sestamibi scan, 77%; magnetic resonance imaging, 77%; selective venous catheterization (SVC) for intact parathyroid hormone, 77%; thallium-technetium scan, 68%; ultrasonography (US), 57%; and computed tomography (CT), 42%. The highest false-positive results were found in MRI, and the highest false-negative results were seen in US. Coexisting thyroid disease can often be a confounding variable in both nuclear imaging and high-resolution ultrasound; interpretation of these exams by experienced radiologist and surgeons is of paramount importance. MRI, thallium-technetium, and technetium sestamibi scans were more sensitive for ectopically located tumors than tumors found in normal positions. They concluded that patients who require a reoperation should receive preoperative localization with the combination of noninvasive imaging methods including US, MRI, CT and sestamibi scans; when used together, they correctly identified abnormal glands in 87% of cases. After a failed primary parathyroidectomy, artifacts from surgical clips placed in the neck often limit the diagnostic quality of CT, although it can be useful for evaluation of altered anatomy [16]. Previous studies have demonstrated limited success in locating mediastinal, retrotracheal, retroesophageal, or small adenomas [2]. If radiographic localization remains equivocal after the previous modalities have been performed, then invasive SVC is recommended. This combination of invasive and noninvasive studies identified abnormal glands in 95% of cases [2, 13]. In one large prospective trial performed at the National Institutes of Health (NIH) , the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed initial procedures for primary hyperparathyroidism were evaluated. The highest false-positive results were seen in ultrasonography, likely due to the identification of lymph nodes within the neck. The study concluded that the single best noninvasive imaging study was the sestamibi scan. Sestamibi with 99mTc is the most commonly used radiotracer for imaging of the parathyroid glands. Sestamibi is taken up by both the thyroid and the parathyroid glands, but hyperactive parathyroid tissue retains the radiotracer longer than normal thyroid tissue on delayed images [16]. As a single test, the sestamibi scan has the advantage of relatively low cost, very good sensitivity, and high specificity. Coexisting thyroid disease such as multinodular goiter, autoimmune thyroiditis, and well-differentiated thyroid cancers can be confounding factors decreasing the identification accuracy of technetium sestamibi. Previous studies have described the accuracy of sestamibi scanning in identifying single adenomas to be approximately 99% [17]. Single-photon emission computed tomography (SPECT) can help to differentiate parathyroid activity from overlying thyroid and has been shown to increase sensitivity of scintigraphic parathyroid imaging [16]. The aforementioned study and several others have concluded the optimal combination would be ultrasound (better intrathyroidal evaluation than sestamibi) and sestamibi (improved mediastinal evaluation) [18, 19]. With regard to invasive studies, venous sampling showed a higher rate of true-positive results versus angiography and should be considered when noninvasive studies are inconclusive, as they are expensive and dependent on the skill of the interventional radiologist [13]. Selective venous sampling has been shown to correctly identify the side of affected gland in >89% of cases [20]. Ultrasound-guided parathyroid FNA provides an alternative technique for identification of abnormal glands, in particular intrathyroidal glands. The addition of on-site PTH analysis aids the ultrasonographer by providing real-time feedback and improves accuracy [6]. Although it has been stated that one should not perform remedial parathyroid surgery unless two preoperative imaging studies are both positive and concordant, many accept a positive sestamibi alone as adequate imaging [6]. Interestingly, investigations have shown that surgeon-performed cervical ultrasonography improved the localization of abnormal parathyroid glands preoperatively [21]. Although ultrasound and scintigraphy are established studies for preoperative localization of parathyroid adenomas, four-dimensional computed tomography (4D-CT) has been increasingly adopted and is routinely used at many hospitals [22]. These images provide anatomical and functional information by incorporating perfusion characteristics of hyperfunctioning glands. One recent study compared scintigraphy to 4D-CT in 40 patients and found that the CT correctly localized 76% of parathyroid lesions in 80% of patients and scintigraphy correctly localized 43% of lesions in 48% of patients. Both modalities missed 20% of lesions. Importantly, in patients with prior failed parathyroidectomies, 4D-CT correctly identified lesions in all five patients, and scintigraphy missed two lesions. The smallest lesion detected by 4D-CT was 4 mm and 10 mm for scintigraphy. 4D-CT exposes the patient to significantly higher doses of ionizing radiation [23]. Four phases may not be necessary; Noureldine et al. found that two-phase and four-phase CT provide an equivalent diagnostic accuracy in localizing hyperfunctional parathyroid glands. The reduced radiation exposure to the patient may make two-phase acquisitions a more acceptable alternative for preoperative localization [24]. To improve unsuccessful reoperative parathyroid surgery, continued research in the radiographic diagnosis of parathyroid lesions is warranted.