Last updated on April 16, 2014 at 1:21 EDT

Primary Hyperparathyroidism: A Current Perspective

August 30, 2008

By DeLellis, Ronald A Mazzaglia, Peter; Mangray, Shamlal

Context.-Primary hyperparathyroidism (P-HPT) is one of the most common of all endocrine disorders. Eighty percent to 85% of cases are due to parathyroid adenomas while hyperplasia and carcinoma account for 10% to 15% and less than 1%, of cases, respectively. The past decade has witnessed remarkable advances in the understanding of the molecular basis of parathyroid hyperplasia and neoplasia. Additionally, imaging studies and the development of the intraoperative assay for parathyroid hormone have transformed the diagnosis and management of patients with these disorders. Objective.-To review the pathology of parathyroid lesions associated with P-HPT, their molecular and genetic bases, including heritable hyperparathyroidism syndromes, and their clinical diagnosis and management.

Data Sources.-Review of pertinent epidemiology, pathology, radiology, and surgery literature on the diagnosis, classification, and treatment of P-HPT.

Conclusions.-Although heritable causes of P-HPT including multiple endocrine neoplasia 1 and 2A and hyperparathyroidism- jaw tumor syndrome account for a minority of cases of P-HPT, advances in the characterization of the affected genes have provided insights into the genetic basis of sporadic parathyroid neoplasms. Alterations in cyclin D1 and loss of heterozygosity of chromosome 11q in adenomas and hyperplasias have provided support for clonality of these lesions. Parafibromin, the protein product of the HRPT2 gene responsible for hyperparathyroidism- jaw tumor syndrome, has been implicated in the development of sporadic parathyroid carcinomas and loss of immunohistochemical expression of this protein has been suggested to be of value in making the diagnosis of parathyroid carcinoma. Sestamibi scanning and ultrasound have revolutionized the planning of surgical approaches and the intraoperative parathyroid hormone assay has become the standard in guiding completion or extension of surgery.

(Arch Pathol Lab Med. 2008;132:1251-1262)

The term primary hyperparathyroidism (P-HPT) refers to the inappropriate or unregulated overproduction of parathyroid hormone (PTH) leading to abnormal calcium homeostasis. High levels of PTH lead to increased renal resorption of calcium, phosphaturia, increased synthesis of 1,24 (OH)^sub 2^D^sub 3^ (which increases interstitial calcium resorption), and increased resorption of bone.1 Typically, patients have evidence of hypercalcemia, hypophosphatemia, hypercalciuria, increased levels of PTH, and normal plasma levels of PTH-related protein. In current clinical practice, P-HPT presents primarily as a disease of middle-aged to older adults with a female-male ratio of 3 to 4:1; however, P-HPT may also present in children or young adults.

The purpose of this article is to provide a review of recent trends in the genetics and epidemiology of P-HPT, the pathology and molecular aspects of this disease, and newer approaches to its diagnosis and treatment.


Prior to the mid 1970s, P-HPT was considered a relatively rare disorder with clinical manifestations dominated by renal and/or bone disease.2 The introduction of automated calcium measurements by multichannel analyzers profoundly changed the landscape of this disorder.3 In 1975, the incidence of P-HPT in Rochester, Minn, was in excess of 100 cases per 100 000 patient years as compared with 15.8 cases in prior decades. Most patients detected by routine serum calcium measurements were either asymptomatic or mildly symptomatic. In succeeding decades, the incidence of P-HPT has fallen in many geographic areas with the most recent data showing an incidence of approximately 15 cases per 100 000 patient years in Rochester.4,5 It has been suggested that the sharp rise and subsequent fall in the incidence of P-HPT was due to the “sweeping” of the population for prevalent cures when calcium was added to the automatic screening panel in 1974.2

The reasons for the apparent fall in the incidence of P-HPT, however, are not at all clear. One suggestion has been that the high prevalence of the disease noted in the 1970s was related to the long- term effects of therapeutic head and neck irradiation for treatment of benign childhood diseases, which was common in the 1930s and 1940s.6 Interestingly, Japanese survivors of the atomic blasts have been shown to have a 4-fold increase in the incidence of parathyroid tumors. It has also been suggested that women with mild underlying P- HPT may have their disease unmasked with the onset of estrogen defi- ciency at the time of menopause, whereas the administration of estrogen in women with mild P-HPT lowers serum calcium.5 Whether the decreased use of estrogens in postmenopausal women will lead to an increasing incidence of P-HPT is unknown. Other factors that have been implicated in the declining incidence of P-HPT include the administration of calcium and vitamin D supplements, both of which suppress the synthesis and secretion of PTH.


Primary hyperparathyroidism may result from adenoma (single gland disease), hyperplasia (multiglandular disease), or carcinoma, which typically involves a single gland. Few cases of apparent P-HPT may result from the paraneoplastic production of PTH by a nonparathyroid tumor, 7,8 whereas most cases of malignancy-associated hypercalcemia result from the paraneoplastic production of PTH-related protein. When defined by clinical and pathologic features, solitary adenomas account for 80% to 85% of cases of P-HPT, hyperplasia for 10% to 15%, and carcinomas for less than 1%. However, if the frequencies of these disorders are determined by intraoperative PTH measurements (discussed later) with postoperative restoration of eucalcemia, hyperplasia becomes considerably less common.9


Parathyroid adenomas are benign neoplasms composed of chief cells, oncocytic cells, or transitional oncocytic cells with frequent admixtures of these cell types10-12 (Figure 1). Most adenomas occur in normally situated glands, but they may occur from near the carotid bifurcation and pericardial sac to the mediastinum and retroesophageal space. Additional locations include the vagus nerve, soft tissue at the angle of the jaw, and the thyroid gland. The average size of adenomas in patients without significant bone disease is approximately 1 g with many less than 0.5 g. Microadenomas weighing less than 0.1 g (microadenomas) are also well documented (Figure 2). Generally, larger adenomas are associated with higher levels of calcium and PTH and are more likely to be symptomatic. Foci of cystic change are particularly common in large adenomas.

Microadenomas are typically nonencapsulated, whereas larger adenomas are often separated from the adjacent rim of normocellular parathyroid gland by a fibrous capsule. The cells of adenomas are arranged in cords, nests, sheets, and follicles and frequently have a palisaded arrangement around blood vessels (Figure 3, A). The nuclei are generally rounded with dense chromatin, and they are usually larger than those of the adjacent normal parathyroid gland. Scattered pleomorphic and hyperchromatic nuclei as well as multinucleate cells are relatively common (Figure 3, B). Mitotic figures may be present in up to 70% of cases,13 and the proliferative fraction as assessed with Ki- 67 is generally less than 4%.14 Tumor cells are positive for cytokeratins, PTH, and chromogranin A, whereas thyroglobulin and thyroid transcription factor 1 are negative. Typically the cells within an adenoma are stained less intensely for PTH than those in the associated rim (if present). Although most adenomas are single, occasional examples of double adenomas have been reported.

Several adenoma variants have been described. Oncocytic adenomas, by definition, are composed of at least 90% of cells with abundant granular eosinophilic cytoplasm10 (Figure 3, C). Lipoadenomas (hamartomas) are composed of abundant stromal elements consisting of mature fat cells with foci of myxoid change, areas of fibrosis, and varying degrees of lymphocytic infiltration. Waterclear cell adenomas have also been described but are exceptionally rare. Occasional adenomas may have a follicular architecture throughout and may be difficult to differentiate from thyroid neoplasms (Figure 3, D). The subject of atypical adenomas is discussed in a subsequent section.

Although initial studies suggested that adenomas were polyclonal proliferations based on patterns of glucose-6- phosphate dehydrogenase expression, more recent studies indicate that they represent clonal expansions.15 Interestingly, a significant proportion of cases of primary and secondary hyperplasia also represent clonal processes. One of the earliest described molecular abnormalities in parathyroid adenomas involved the cyclin D1 (CCND1)/ PRAD1 oncogene (11q13). The product of this gene encodes a 35-kDa holoenzyme that phosphorylates and inactivates the retinoblastoma protein and thereby promotes the progression of cells through the G^sub 1^-S phase of the cycle.16 Rearrangements of the CCND1 gene, which occur as a result of pericentromeric inversion, lead to the placement of the 5′ regulatory sequence of the PTH gene in proximity to the CCND1 gene. The 11q13 chromosome breakpoint can be positioned within 1 to 2 kb of CCND1 or as much as 300 kb upstream or further in different tumors.15 The resultant rearrangement leads to overexpression of cyclin D1 protein. Although rearrangements were initially described in only 5% of adenomas, overexpression of the gene occurs in a significantly higher proportion of cases (20%- 40%). Other mechanisms resulting in overexpression of CCND1 include amplification, rearrangement with other enhancers or promoters, or transcriptional activation.15 The MEN1 gene (11q13) is a tumor suppressor gene that plays an important role in the pathogenesis of parathyroid adenomas.17,18 The protein product of the gene, menin, is a 610 amino acid protein, which is involved in transcriptional regulation involving JunD. Additional proteins that interact with menin include Smad3 and NF-kappaB.19,20 Loss of heterozygosity (LOH) of 11q13 has been demonstrated in 25% to 40% of adenomas with approximately 50% of these cases being associated with somatic homozygous mutations of the MEN1 gene.15,21,22 These findings suggest that an additional tumor suppressor gene on 11q may be the functional target of some of these acquired deletions.

A number of other genes, including RET, the vitamin D receptor and the calcium sensing receptor (CaSR), have been studied for pathogenetic mutations in adenomas, but none has been found. The CaSR gene, however, which when partially or completely inactivated can cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, must still be considered as having a potentially important secondary role in the genesis of these tumors, which typically have increased PTH-calcium set points.15

As expected, comparative genomic hybridization studies have demonstrated loss of 11q as the most frequent abnormality in parathyroid adenomas. In addition, losses of 1p, 6q, 9p, 11p, 13q, and 15q and gains in 7, 16p, and 19p occur commonly in these tumors.23


Chief cell hyperplasia is currently defined as an absolute increase in parenchymal cell mass, which occurs as result of the proliferation of chief cells, oncocytes, and transitional oncocytes in multiple parathyroid glands.11,12 The enlargement of the glands is symmetric in approximately 50% of the cases and asymmetric in the remainder. The distinction between asymmetric hyperplasia and adenoma may be extremely difficult, if not impossible, by standard morphologic criteria. The weight of individual glands can vary from 150 mg to more than 10 g. The cells are distributed in diffuse and/ or nodular patterns and the amount of stromal fat is usually markedly decreased (Figure 4). In some instances, however, there may be abundant stromal fat (lipohyperplasia). Foci of cystic change with fibrosis and hemosiderin deposition may be prominent, particularly in larger lesions.

Chief cell hyperplasia occurs sporadically in approximately 75% of cases, whereas 25% are heritable.24 With the development of increasingly more sensitive diagnostic molecular methods, the proportion of recognized familial cases is expected to increase further. Familial HPT is a clinically and genetically heterogeneous group of disorders that includes multiple endocrine neoplasia (MEN) type 1, MEN2, familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism, hyperparathyroidism- jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, and autosomal dominant mild hyperparathyroidism or familial hypercalcemia with hypercalciuria (Table).

MEN1 is inherited as an autosomal dominant trait characterized by the development of multiglandular parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, and pituitary adenomas.25 Additional tumors reported in these patients include neuroendocrine tumors of the thymus, lung, and stomach, adrenocortical tumors, multiple lipomas, and facial angiomas and collagenomas. Parathyroid disease occurs in more than 90% of patients, gastroenteropancreatic tumors in 60%, and pituitary tumors in 30%.26 Although the parathyroid disease has been classified traditionally as multiglandular hyperplasia, more recent studies indicate that these are clonal proliferations. Multiple endocrine neoplasia occurs as the result of germline MEN1 mutations, which are spread over the entire coding and intronic regions with more than 400 different recognized sites.20 The development of parathyroid tumors and other tumors in the syndrome occurs as a result of the inactivation of the wild-type allele at the somatic level.

MEN2 occurs as an autosomal dominant trait characterized by the development of C-cell hyperplasia and medullary thyroid carcinoma, adrenal pheochromocytomas, and parathyroid hyperplasia.27 The thyroid tumors occur in virtually all patients with the syndrome, whereas adrenal medullary abnormalities occur in approximately 30% of affected patients. In contrast to the high frequency of HPT in MEN1, HPT occurs in 20% to 30% of patients with MEN2A but does not occur in MEN2B or familial medullary thyroid carcinoma. Dominant activating germline mutations of the RET oncogene (10q11.2) are responsible for the development of the syndromes. The most common mutations associated with MEN2A occur in codon 634, which represents the most frequently mutated codon in the syndrome.27

Familial hypocalciuric hypercalcemia is inherited as an autosomal dominant trait and is characterized by increased or normal levels of PTH24 (Table). This disorder occurs as a result of a partial resistance to the effects of calcium on the parathyroid glands and kidney. The disease (FHH type 1) is due most frequently to loss of function mutations of the CaSR gene on 3q21.1.28 Rare types of FHH (types 2 and 3) have been traced to mutations on chromosome 19. Before the recognition of this entity, many patients with FHH were subjected to unnecessary parathyroidectomy because they were thought to be affected by other types of P-HPT. However, the resected glands were either normocellular or slightly hypercellular.

Neonatal severe hyperparathyroidism represents the homozygous form of FHH.28 The disorder may be manifested at birth or within the first 6 months of life. Affected patients must be treated emergently with the resection of the hyperplastic glands.

The HPT-JT syndrome is a rare autosomal dominant disorder characterized by hyperparathyroidism and fibroosseous lesions of the mandible or maxilla.29,30 Affected patients may also have evidence of a variety of renal lesions including, cysts, hamartomas, renal cell carcinoma, and Wilms tumor. Hyperparathyroidism, which becomes apparent in late adolescence or in older individuals, is due to the presence of multiple adenomas. Some of these tumors may be cystic and approximately 10% to 15% of the patients have parathyroid carcinomas.29-31 Mutations of the HRPT2 gene (1q25-32), a tumor suppressor gene, which encodes parafibromin, are responsible for the development of the syndrome.32

Familial isolated hyperparathyroidism is characterized by the presence of benign multiglandular parathyroid disease unassociated with the presence of other endocrine tumors.33 The familial isolated hyperparathyroidism phenotype has been associated with mutations in the MEN1 and CaSR genes and rarely with the HRPT2 gene. In a study of 28 unrelated patients, Warner et al34 found 5 (23%) with MEN1 mutations and 4 (18%) with CaSR mutations; however, there were no patients with HRPT2 mutations. These observations underscore the need for the identification of other genes that may be involved in the development of familial isolated hyperparathyroidism.

Familial hypercalcemic hypercalciuria or autosomal dominant mild hyperparathyroidism has been described in a single kindred and was due to an inactivating mutation in the cytoplasmic tail of the CaSR gene.35 Subtotal parathyroidectomy demonstrated hyperplasia or adenoma and cured the hypercalcemia in 7 of 9 patients.


Parathyroid carcinoma is an uncommon tumor, which most often appears as a large mass that is densely adherent to the surrounding soft tissues or thyroid gland.36 The diagnosis of malignancy should be restricted to those cases that show invasion of adjacent soft tissues or thyroid gland, blood vessels, or perineural spaces and to those tumors with documented metastases37 (Figure 5, A through C). The diagnosis of parathyroid carcinoma is challenging. Fibrous band formation within the tumor is common, but by itself, this feature is insufficient for the diagnosis of malignancy. Similarly, the presence of mitotic activity is insufficient for the diagnosis of malignancy because mitoses are relatively common in benign parathyroid proliferations. Most carcinomas have a solid growth pattern with tumor cells arranged in diffuse patterns, small nests, or trabeculae. There is generally mild to moderate nuclear pleomorphism, but some tumors may be indistinguishable from adenomas. One approach to the differential diagnosis of adenomas has involved the use of MIB-1 to assess cell proliferation.14,38 The proliferative fraction of carcinomas is higher than that of adenomas, but the overlap in equivocal cases has limited the usefulness of this approach. An additional approach has involved the use of antibodies to p27, a protein that inhibits cell cycle dependent kinases. As compared with adenomas, carcinomas demonstrated a 3-fold decrease in p27 expression.39 These findings have suggested that low p27 and high MIB-1 scores may be useful in the discrimination of parathyroid carcinomas and adenomas.

Comparative genomic hybridization studies have demonstrated losses of 1p and 13q in more than 40% of cases of parathyroid carcinoma.40 Common regions of loss include 1p21-22 (41%), 13q14- q31 (41%), 9p21-pter (28%), 6q22-q24 (24%), and 4q24 (21%), whereas regions of gain involved 19p (45%), Xcq13 (28%), 9q33qter (24%), 1q31- q32 (21%), and 16p (21%). Kytola and colleagues40 suggested a model based on these observations characterized by early gains of Xq and 1q followed by loss of 13q, 9p, and 1p and gain of 19p. Losses of 1p, 4q, and 13q and gains of 1q, 9q, 16p, 19p, and Xq were significantly more common in carcinomas than in adenomas. Interestingly, loss of 11q13, the most common abnormality of adenomas, was undetectable in this study. This finding has suggested that adenomas developing along the MEN1 pathway have minimal potential for progression into carcinomas.40 With fluorescence in situ hybridization, Erickson et al41 confirmed the lack of chromosome loss in carcinomas but noted chromosome gains in 3 of 4 patients who died of metastatic parathyroid carcinomas. Haven et al,42 on the other hand, demonstrated 1q and 11q LOH in 55% and 50% of parathyroid carcinomas with combined losses of 36%. Valimaki and colleagues43 demonstrated 1p LOH in 43% of adenomas; 60% of these cases harbored alterations of either 1p, 11q13, or both. Loss of heterozygosity in sporadic adenomas occurred frequently on the distal part of 1q, whereas deletions of 1p in carcinomas occurred more proximally. These observations suggest that 1p may harbor at least 2 different suppressor genes that may be involved in parathyroid tumorigeneses.

Several groups have demonstrated LOH on chromosome 13q, a region that includes RB and BRCA2, in parathyroid carcinomas. In the series reported by Cryns et al,44 11 of 11 specimens from patients with parathyroid carcinoma and 1 of 19 adenomas lacked an RB allele. Correlative immunohistochemical studies demonstrated a complete or predominant absence of RB expression in carcinomas, whereas none of the adenomas had abnormal RB staining patterns. BRCA2 has also been suggested as a potential suppressor gene in these tumors.45 However, the contribution of both RB and BRCA2 to the development of carcinomas has been controversial. In a recent study by Cetani et al,46 LOH for at least one marker of the RB1 locus was found in 6 of 6 carcinomas, whereas LOH for BRCA2 was found in 3 of 5 cases. In the same series, LOH of RB and BRCA2 was demonstrated in 28.8% and 17.4%, respectively, of adenomas.

Shattuck et al47 recently performed direct sequencing of parathyroid carcinomas that demonstrated LOH of RB or BRCA2 and were unable to find microdeletions, insertions, or point mutations of either gene. They concluded that neither RB nor BRCA2 were likely to act as tumor suppressor genes in carcinomas. However, these results do not exclude the possibility that the decreased RB function in carcinomas, whether secondary or because of epigenetic effects, may play a role in tumor development. It is also possible that other genes on chromosome 13 may be implicated in the development of parathyroid carcinomas.

The role of the HRPT2 gene (1q25-q32) in the pathogenesis of sporadic parathyroid carcinomas was first demonstrated by Howell et al in 2003.48 Shattuck et al49 in the same year demonstrated somatic mutations in the HRPT2 gene in 10 of 15 parathyroid carcinomas. These mutations were predicted to inactivate the encoded parafibromin protein. Of particular interest in this study was the observation that the mutations in 3 of the patients were identi- fied in the germline. The latter finding suggested that a subset of patients with apparent sporadic carcinomas carry germline mutations in the HRPT2 gene and may have the HPT-JT syndrome or a variant of this syndrome. There are several important implications of this study. First, all patients with parathyroid carcinoma should have jaw and kidney imaging studies. If the HPT-JT syndrome is diagnosed, family members should undergo screening studies. Second, patients with parathyroid carcinomas should be tested for HRPT germline mutations. If mutations are detected, family members should be offered genetic counseling and molecular screening studies.

Loss of parafibromin immunoreactivity has been reported as a marker for parathyroid carcinoma by Tan et al50 (Figure 6, A through C). These workers noted that loss of parafibromin nuclear immunoreactivity had a 96% sensitivity and 99% specificity for the definitive diagnosis of parathyroid carcinoma. In addition to parafibromin loss in carcinomas, this protein was also absent from HPT-JT associated adenomas. Similar results have been reported by Gill et al51 and Juhlin et al.52 However, in our experience, loss of parafibromin staining has been noted in a subset of adenomas unassociated with the HPT-JT syndrome, whereas some carcinomas have shown positive staining (S.M. and R.A.D., unpublished observations, 2007) (Figure 6, C).


Atypical adenomas of the parathyroid glands represent a controversial entity. These tumors have some of the features of parathyroid carcinomas but lack unequivocal evidence of invasive growth (peritumoral vascular invasion, perineural invasion, invasion of adjacent soft tissues or thyroid).12,37 Features that have been considered atypical in these tumors are intratumoral banding fibrosis, mitotic activity, trabecular growth, adherence of tumor to peritumoral soft tissues or thyroid gland, and presence of tumor cell within the surrounding capsule (Figure 7). Tumors with these features have also been categorized as “equivocal.” Patients with atypical adenomas generally present with calcium levels that are intermediate between those seen in patients with carcinomas and adenomas. Based on studies reported in the literature and our own observations, the majority of atypical adenomas pursue a benign clinical course.53 Interestingly, the molecular phenotype of atypical adenomas is intermediate between that of adenomas and carcinomas. Stojadinovic et al54 reported that the phenotype p27(+), bcl2(+), Ki-67(-), mdm2(+) was present in 76% and 29% of typical adenomas and atypical adenomas, respectively, and in no cases of parathyroid carcinoma.


Advances in the fields of nuclear medicine, ultrasound, and intraoperative hormone measurement have made significant impacts on the evaluation and management of patients with sporadic P-HPT during the past decade. Currently, surgeons are evaluating more patients referred for treatment and these patients have lower serum calcium values than they had in the past. Indications for surgical treatment of asymptomatic hyperparathyroidism have been established by a National Institutes of Health Consensus Conference,55 but many investigators have shown that these indications may be too limited.56,57 Therefore, up to 50% of patients undergoing parathyroidectomy may not meet strict National Institutes of Health criteria. Detailed questioning and analysis reveals that the majority of patients suffer from nontraditional symptoms such as fatigue, memory loss, arthralgias, myalgias, depression, and insomnia, and most will experience significant improvement after parathyroidectomy.56,57

The role of preoperative localization studies to identify enlarged parathyroid glands has been evolving during the last 3 decades. Some institutions were performing rudimentary nuclear medicine scans in the 1980s with technetium Tc 99m. The initial goals of localization were to provide a roadmap for surgical exploration, with the acknowledgment on the part of surgeons that the tests were not perfect, and 4-gland parathyroid exploration was still the gold standard to ensure surgical cure by removal of all abnormal parathyroid tissue.

Sestamibi scanning, as a means of localizing parathyroid adenomas, was first described in 1992 by Taillefer et al.58 Because the sestamibi isotope is taken up by metabolically active mitochondria, it highlights both the thyroid and parathyroid tissue early after injection, but on delayed imaging at 2 to 3 hours, it washes out of the normal thyroid tissue but is retained by the abnormal parathyroids, thereby enabling their identification. Modifications of the original sestamibi scan protocols include the use of radioactive iodine to allow for subtraction of the thyroid image (Figure 8), as well as single photon emission computed tomography imaging, which provides a 3- dimensional view of the neck, enhancing the ability of radiologists and surgeons to pinpoint the location of an abnormal gland. The latter procedure has been shown to be the most accurate nuclear medicine scan for parathyroid localization.59

Studies evaluating the accuracy of sestamibi scanning for the identification of parathyroid adenomas have established a sensitivity ranging from 73% to 87% for single adenomas, but significantly less success for the identifi- cation of parathyroid hyperplasia ranging from 37% to 44%.60,61 Because of this shortcoming, sestamibi preoperative localization was inadequate to permit focused-approach surgery, when traditionally 10% to 15% of patients with P-HPT have had hyperplasia.61 The advent of the rapid intraoperative PTH (IOPTH) assay with its reported accuracy of 97% proved to be a major advance for surgeons because they now had a tool that could reliably confirm or refute the prediction of the preoperative localization study.

Preoperative head and neck ultrasound has joined the ranks of sestamibi scanning for preoperative parathyroid localization during the past decade (Figure 9). Recent studies report sensitivities in patients with sporadic hyperparathyroidism ranging from 57% to 77%.61-66 Solorzano et al66 demonstrated the role of ultrasound as the sole localizing procedure and demonstrated a sensitivity of 77%, which was equivalent to sestamibi scanning results in that study. The combination of both procedures raised the percentage of correctly identified glands to 90%. For patients with an incorrectly identified gland on sestamibi, the ultrasound was successful in 56%.64 The shortcomings of ultrasound are revealed in patients with ectopic glands, in whom the sensitivity is 25% or less,64 as well as in patients with multigland disease, in whom the sensitivity is only 25% to 30%.

The description by Irvin et al67 of a rapid IOPTH assay in 1991 made possible the real-time confirmation of surgical cure. The initial series of 63 cases published in 1993 reported a sensitivity of 96%, a specificity of 100%, and overall accuracy of 97%.68 Multiple studies have confirmed the ability of IOPTH to guide the surgeon’s intraoperative decision making by accurately predicting whether or not additional hypersecreting glands remained in the neck after removal of the gland or glands identified by preoperative localization. Thus armed, the surgeon using a focused approach could appropriately explore the contralateral neck in the 15% to 20% of patients with multigland hyperplasia or double adenomas that are often missed by sestamibi. This brought the long-term success rate of the focused approach into line with that of a traditional 4- gland exploration.69-71 Specifically, a drop in IOPTH of 50% from the baseline or preexcision value, at 10 minutes after gland excision, was established as the criterion by which the surgeon could safely conclude that all abnormal parathyroid glandular tissue had been removed, without having to identify all 4 glands. Using these criteria, cure rates, as defined as normocalcemia at 6 months postoperatively, have been 95% or greater.

If a single abnormal focus of sestamibi uptake is identified, the surgeon begins by exploring that side of the neck, and obtaining PTH values pre- and post-adenoma excision. If the PTH falls by 50% or more, or into the normal range, surgery is concluded; however, if the PTH remains inappropriately elevated, further exploration is undertaken with the expectation of finding multigland disease. Fortunately, identification of all 4 glands can be performed safely through the same 2.5- to 3-cm incision that was used for the unilateral exploration, because these incisions should be centered on the midline for patients who have not been explored previously. Benefits of the focused approach are based on the fact that dissection is carried out unilaterally, theoretically decreasing the risk of recurrent laryngeal nerve injury and permanent hypoparathyroidism. Other benefits to the patient include the potential for outpatient surgery and similar success rates when compared with 4-gland exploration.72

A focused approach should be performed in patients with P-HPT who have a preoperative sestamibi scan and/ or ultrasound that predicts a single enlarged gland. If more than one gland appears abnormal on either of these tests, or if the tests contradict each other by predicting contralateral disease, a traditional 4-gland exploration is recommended. In this situation, some practitioners may begin exploration unilaterally and conclude the operation if the IOPTH decreases by more than 50% after removal of the first abnormal gland. The long-term outcome of such an approach is not known, because 15% of patients will have additional abnormal glands, even when the IOPTH had dropped appropriately.73 In cases in which the sestamibi scan and/or ultrasound is negative for localization of an enlarged parathyroid gland, 4-gland exploration is recommended; negative localization studies are more commonly found in patients with hyperplasia.

The long tradition of parathyroid surgery for P-HPT was begun by Dr Felix Mandel in Vienna in 1925. The successful operation performed on a Viennese streetcar operator revealed a single parathyroid adenoma and 3 normal glands. From that point, 4-gland exploration was considered standard, and multiple large series established the rates of single adenoma, double adenoma, and 4- gland hyperplasia at approximately 80%, 5%, and 15%, respectively.74,75 The determination of gland abnormality intraoperatively had always originated with the visual inspection by the surgeon. Based on gland size, color, and firmness, surgeons strive to make a judgment as to whether a gland is normal, hyperplastic, or adenomatous. Thus, the published rates for single versus multiple gland disease had in the past reflected the number of “abnormal” glands removed at the time of surgery and not necessarily glandular pathology or physiology. However, since the introduction of IOPTH, an increasing number of surgeons are abandoning the traditional 4-gland exploration.

Of considerable interest is the changing frequency of single and multigland disease that has accompanied the move from 4-gland exploration to the focused surgical approach in patients with P- HPT. The traditionally quoted frequency of multigland disease from the large series of 4-gland exploration ranged from 14% to 21%.75- 77 In the era of focused parathyroid surgery, with the majority of patients undergoing unilateral exploration, the prevalence of multigland disease has fallen to between 5% and 10%. In a consecutive single surgeon series looking at 656 cases performed either by a standard 4-gland approach or by a minimally invasive approach, the rates of double adenoma and hyperplasia were 11% and 7%, respectively, in the patients undergoing 4-gland exploration and only 5.1% and 1.6%, respectively, in the focused-approach group.72 These findings underscore the reality that approximately 15% of patients have additional enlarged glands that are not identified by sestamibi, ultrasound, or IOPTH but would have been discovered and excised had a 4-gland exploration been performed.73 Because even the best series typically has follow-up data on eucalcemia only out to 6 months, the long-term cure rates for parathyroidectomy via a focused approach remain unproven, and the question remains as to whether enlarged glands that are not hypersecreting at the time of first surgery will cause recurrent hyperparathyroidism in the future.

Some of the longest follow-up of patients who have had focused- approach surgery with IOPTH has been published by the Endocrine Surgery Department at the University of Miami. In nearly 300 patients with 6-month postoperative calcium levels, the cure rates were 98%. Success in this series was quite high despite the discovery of multigland disease in only 3.4% of patients.78

Unfortunately, there continues to be a small number of failures with the use of IOPTH. In 2% to 3% of cases there will be a false- positive drop of more than 50% from the baseline or pre-excision level to the 10-minute postexcision level, which incorrectly leads the surgeon to conclude the operation, leaving additional hyperfunctioning glands and a high likelihood of persistent or recurrent disease.69,70 These series and others also report the 2% to 3% rate of a false-negative drop in IOPTH levels, when the level fails to fall within 10 minutes even though all hyperfunctioning tissue has been removed, incorrectly prompting the surgeon to explore further. There also has been reported a steeper slope of decay for IOPTH in single versus multigland disease.79 Because of these inaccuracies as well as the existence of anatomically enlarged glands that may not yet be hypersecreting, some surgeons continue to advocate 4-gland exploration as the best approach in all patients.73

In recent years some investigators have suggested that focused- approach parathyroidectomy can successfully be performed without the use of IOPTH assays in patients with unequivocal preoperative localizing studies.80,81 However, most surgeons performing unilateral exploration continue to use IOPTH as an adjunct to confirm operative success, which in the best of hands is increased from 94% to 98% with the assay,82 and long-term success with this technique in a series of 423 patients with a median of 27 months follow-up was 97%.79 In that group of patients, use of IOPTH changed operative management in 17% of patients and was considered indispensable for the 20% of patients with incorrect sestamibi scans.83 Most series con- firm that in patients with an inaccurate sestamibi scan, IOPTH will alert the surgeon to the presence of additional abnormal parathyroid glands and lead to operative success in more than 95% of cases.84

For those patients with known multigland disease, including renal failure patients with secondary and tertiary hyperparathyroidism, as well as patients with MEN and familial hyperparathyroidism, the best operative strategy is a 4-gland exploration with either subtotal parathyroidectomy or total parathyroidectomy and autotransplantation. Preoperative localizing studies lack sensitivity and are unnecessary but are often obtained to search for ectopic glands. Because up to 20% of patients will have a fifth parathyroid gland, often located in the thymus, routine thymectomy is recommended as part of this procedure. The use of IOPTH is not mandatory in these cases but may be helpful in predicting surgical success.85-87

In patients with persistent or recurrent hyperparathyroidism, preoperative localization not only with sestamibi and ultrasound but also with computed tomography scan, magnetic resonance imaging, and selective venous sampling may be used to identify missed or ectopic glands in a previously operated neck. Because scar from the original exploration increases the difficulty of dissection, as well as the risk of complications, it is optimal to confidently identify the abnormal parathyroid(s), especially in cases of prior bilateral exploration. If a single gland has been identified, surgical exploration should focus on its removal without further dissection. In these cases, it is reassuring to use IOPTH for confirmation of a surgical cure.

In summary the last decade has witnessed a dramatic shift in the surgical approach for P-HPT, with a concomitant decrease in the rate of multigland hyperplasia because of the adoption of a focused- approach technique. Although this procedure produces rates of cure equivalent to traditional 4-gland exploration, it unquestionably leaves enlarged glands behind in up to 15% of patients. Longterm follow-up will be necessary to determine whether late recurrences will develop.


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Ronald A. DeLellis, MD; Peter Mazzaglia, MD; Shamlal Mangray, MD

Accepted for publication January 30, 2008.

From the Departments of Pathology (Drs DeLellis and Mangray) and Surgery (Dr Mazzaglia), Rhode Island Hospital and the Miriam Hospital and the Warren Alpert Medical School of Brown University, Providence, RI.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ronald A. DeLellis, MD, Department of Pathology-APC 12- 106, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (e- mail: rdelellis@lifespan.org).

Copyright College of American Pathologists Aug 2008

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