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Editorial |
Department of Medicine College of Physicians & Surgeons Columbia University New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Shonni J. Silverberg, Department of Medicine, College of Physicians, Surgeons, 630 West 168th Street, New York, New York 10032.
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in the general population. The disease has an incidence as high as 1 in 1000 individuals and occurs more commonly in women than in men (3:1). In approximately 80% of cases of PHPT, a single benign adenoma is the cause of abnormal parathyroid function. In 15–20% of cases, PHPT is due to hyperplasia of all four parathyroid glands. Rarely, multiple adenomas can be seen. In less than 1% of cases, the most scarce and deadly presentation of PHPT occurs, namely that of parathyroid carcinoma (1).
The clinical presentation of benign PHPT has undergone a sea change over the past 30 years. The disease used to be a symptomatic disorder in which the hallmarks were kidney stones and the classical skeletal abnormality osteitis fibrosa cystica (2). With the advent of the multichannel autoanalyzer in the early 1970s, the typical presentation of PHPT evolved from that of a symptomatic disorder to one without clear symptoms in the vast majority of patients. Most symptomatic patients today have biochemically mild disease and nephrolithiasis.
Although modern PHPT is largely an asymptomatic disease, it still occurs in the older, classical symptomatic form. Instead of the serum calcium levels hovering within 1 mg/dl of the upper limit of normal, hypercalcemia, in this symptomatic phenotype, can be more alarming, extending into the life-threatening range. The PTH level in these situations is similarly higher than the typical 1.5- to 2.0-fold elevation. These more severely affected patients have clear signs and symptoms of PHPT. Complications may include nephrolithiasis and nephrocalcinosis; bone pain, fractures, or reduced bone density; as well as neuropsychological and gastrointestinal abnormalities.
Although the highly symptomatic presentation of PHPT may be attributed to a single very active benign parathyroid adenoma, occasionally the underlying disorder is not benign. There are several features that suggest a diagnosis of parathyroid cancer. These patients tend to be the most severely affected of PHPT patients, with serum calcium concentrations that are often greater than 15 mg/dl and PTH levels by immunoradiometric assay up to or exceeding 1000 pg/ml. There may be a mass in the anterior neck. Renal (60%) and skeletal (73%) involvement are common and are often seen concurrently (1). Demographic differences also distinguish between benign and malignant disease. The incidence of parathyroid cancer does not favor women but is rather evenly matched between the sexes, and the age of onset is approximately 10 years earlier than in benign disease (mid-40s instead of the mid-50s).
The management of parathyroid cancer is en bloc surgical extirpation of the neoplasm and any adjacent tissue invaded by tumor. A high index of suspicion for the diagnosis of cancer is critical, because the best outcome is associated with complete surgical resection at the initial operation. Incomplete resection will result in recurrences that ultimately lead to death due to intractable hypercalcemia. There is no medical cure for parathyroid carcinoma; although bisphosphonates and calcimimetic agents control hypercalcemia, chemotherapy and radiotherapy are woefully ineffective.
There is no way to foretell before parathyroid surgery whether the presentation of severe PHPT is due to a very active benign parathyroid adenoma or to its malignant counterpart. At the time of surgery, parathyroid cancer can have a characteristic gross, stony-hard appearance supported by clear histological features such as uniform sheets of cells in a lobular pattern, separated by dense fibrous trabeculae, with mitotic figures in tumor cells and capsular or vascular invasion (3). However, the diagnosis of a parathyroid malignancy is notoriously difficult to make on both gross and histological examination. It is often impossible to distinguish between benign and malignant disease without clear evidence that the tumor is invasive. Local (thyroid bed, cervical lymph nodes) or distant (lung, liver, bone, lymph node) metastases firmly establish the diagnosis of parathyroid malignancy. However, at this stage cure is impossible. Until now, no genetic markers that reliably distinguish carcinoma from adenoma have been identified.
Recently, mutations in a newly identified tumor suppressor gene, HRPT2, have been associated with the development of parathyroid carcinoma in hyperparathyroidism-jaw tumor syndrome (HPT-JT) and in sporadic parathyroid carcinoma (4). The HPT-JT syndrome is a rare autosomal disorder consisting of parathyroid tumors, ossifying fibromas of the mandible and maxilla, and occasionally renal hamartomas and cystic kidney disease. The HRPT2 gene has 17 exons and maps to the chromosomal region 1q24-q32. For the gene to be inactivated, two "hits" must occur: first an inactivating mutation on one allele, then a second hit with either a mutation in the remaining normal allele or deletion of the remaining normal allele (identified in the tumor as loss of heterozygosity of polymorphic markers located near the gene). HRPT2 normally encodes the 531-amino-acid protein parafibromin (named for parathyroid tumors and jaw fibromas). Parafibromin is present in other tissues in addition to the parathyroid (e.g. adrenal, kidney, heart, and skeletal muscle) and probably functions normally to inhibit cell proliferation (5) and regulate transcriptional control (6).
There is a sizable body of evidence that HRPT2 mutations are associated with parathyroid cancer. Germline HRPT2 mutations were found in 14 of 24 cases of HPT-JT; six of the 14 families, or 43%, had parathyroid cancer (4). Somatic mutations have been detected in four of four tumors of sporadic parathyroid carcinomas, in five of five cases of HPT-JT, and in one case of familial isolated hyperparathyroidism (7). Shattuck et al. (8) found HRPT2 mutations in 10 of 15 patients with apparently sporadic parathyroid carcinoma; three of the patients had germline HRPT2 mutations. Cetani et al. (9) found HRPT2 mutations in six of seven patients with parathyroid cancer, although the mutation was not detected in one HPT-JT kindred. Moreover, loss of immunoreactivity to parafibromin, the gene product of HRPT2, has been shown to have high sensitivity and specificity for diagnosing parathyroid carcinoma (10).
At the same time, HRPT2 mutations have only rarely been reported in parathyroid adenomas. Somatic inactivating mutations were reported in 4% of sporadic parathyroid adenomas (2 of 47), none of which had germline mutations (4). However, these were cystic adenomas, a characteristic of many lesions in HRPT2-associated HPT-JT. No HRPT2 mutations were detected in 25 patients with sporadic adenomas in another study (7). In a different study, of 35 adenomas that were previously selected to not have deletion of one of the MEN1 genes, one patient had a somatic HRPT2 mutation (9).
In this issue of the journal, Krebs et al. (11) studied 60 sporadic parathyroid adenomas without any pathological suggestion of malignant features. The authors directly sequenced the coding and flanking splice-junctional regions of all HRPT2 exons, and no intragenic HRPT2 mutations were detected. This study is therefore the first to report on the absence of HRPT2 mutations in a large sample of benign tumors. Although tests for HRPT2 or for its gene product parafibromin are not commercially available, these tools could be an appealing way in the future to distinguish between parathyroid carcinoma and adenomas at the time of initial surgery.
Will HRPT2 be a useful screening test? The mutation is undoubtedly present in the setting of parathyroid cancer. However, the mutation has not been uniformly found in all parathyroid cancer patients, or even in all patients with genetic hyperparathyroid syndromes. In one study (4), it was not detected in 42% (10 of 24) of kindreds with known HPT-JT and in another (9) it was absent in the one HPT-JT kindred studied, as it was in a kindred with familial isolated hyperparathyroidism with associated parathyroid carcinoma (12). Similarly, Shattuck et al. (8) did not find a mutation in 33% (5 of 15) of parathyroid cancer patients. As noted by Krebs et al. (11), the absence of HRPT2 mutations in these cases could be explained by noncoding mutations in the HRPT2 promoter or another regulatory region, which would inactivate the gene but would escape detection. Moreover, having the mutation does not unequivocally guarantee disease; 10% of HPT-JT mutation carriers are clinically silent in adulthood (13), and the mutation was found in several adenomas as mentioned above, although they were, admittedly, selected for unique histological or genetic features (4, 9).
The diagnostic utility of HRPT2 screening must also be seen in the context of the very low prevalence of parathyroid carcinoma. This lowers the probability of cancer, even if the mutation is present (the positive predictive value). HRPT2 screening might not ultimately find its greatest applicability in a population with asymptomatic PHPT, but rather it would be informative in the evaluation of high-risk populations. One such group would be those patients with severe PHPT. We do not know whether the population studied by Krebs et al. (11) had severe or mild PHPT. HRPT2 testing needs to be evaluated not only in populations with confirmed benign disease and clear-cut cancer, but also in patients with severe benign PHPT who have clinical manifestations similar to and easily confused with parathyroid cancer. It would also be of interest to investigate HRPT2 status in another high-risk group: patients with adenomas that are noninvasive but have histological features suggestive of malignancy. The test might also be valuable in the evaluation of those unusual manifestations of PHPT that have features suggestive of parathyroid cancer. Among these are patients with atypical adenomas whose tumors invade into but not through the capsule and those with parafibromatosis, in which multiple recurring nodules of hyperfunctioning parathyroid tissue are found in the neck and mediastinum.
HRPT2 screening will thus probably be most useful in those patients in whom one has a clinical suspicion for parathyroid cancer before or after initial surgery. If the mutation is present, the likelihood of malignancy is certainly increased. More aggressive surgery and family screening would then be indicated. In patients with severe biochemical and clinical manifestations, aggressive surgery should be pursued even if the mutation is not found, because it is not detected in all cancers. Nevertheless, the absence of the mutation might provide grounds for less aggressive follow-up and family screening. HRPT2 status would thus be a valuable piece of information to add to the conventional clinical parameters of parathyroid cancer. This test will be especially helpful if it directs us to an aggressive surgical approach when it is needed, because that is ultimately the only cure for this devastating disease.
Footnotes
Abbreviations: HPT-JT, Hyperparathyroidism-jaw tumor syndrome; PHPT, primary hyperparathyroidism.
Received July 14, 2005.
Accepted July 28, 2005.
References
This article has been cited by other articles:
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  F. Cetani, E. Ambrogini, P. Viacava, E. Pardi, G. Fanelli, A. G. Naccarato, S. Borsari, M. Lemmi, P. Berti, P. Miccoli, et al. Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur. J. Endocrinol., May 1, 2007; 156(5): 547 - 554. [Abstract] [Full Text] [PDF]
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