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Editorial |
Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892
Address all correspondence to: Stephen J. Marx, Metabolic Diseases Branch/National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9C-103, MSC 1804, Bethesda, Maryland 20892-1804. E-mail: stephenM{at}intra.niddk.nih.gov.
Endocrinologists, oncologists, and other clinicians have long benefited from highly sensitive RIAs to aid in surveillance for a wide variety of endocrine cancers. Secreted products of endocrine cancers, whether mature hormones such as calcitonin, prohormones like thyroglobulin, or by-products such as the C-peptide of insulin, can be detected by RIA with exquisite sensitivity. Hormone-related screening can provide invaluable information about the early emergence, recurrence, total burden, and localization of potentially fatal endocrine malignancies. This is particularly useful in the setting of familial disease, where tumors are more likely to be at young ages, multiple, and highly penetrant. In addition to serum calcium measurements, the immunoradiometric assay for PTH has been especially helpful in monitoring for parathyroid tumors. The potential for increased sensitivity by adding tumor imaging is highlighted by Guarnieri et al. (1) in this issue; they report screening for parathyroid tumors in a large kindred with familial isolated hyperparathyroidism (FIHP) caused by germline HRPT2 mutation.
Germline mutation of HRPT2 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome (HPT-JT), providing a basis for linkage analysis and identification of the gene (2). HRPT2 encodes parafibromin, a 531-amino-acid putative tumor suppressor protein. The C-terminal region of parafibromin demonstrates sequence homology to Cdc73p, a component of the yeast RNA polymerase II-associated Paf1 complex, and recent evidence suggests that parafibromin interacts with the homologous human complex (3, 4). The N-terminal region of parafibromin may bind to ß-catenin and mediate other effects via the Wnt signaling pathway (5).
HPT-JT is an autosomal dominant syndrome with high but incomplete penetrance. The major features are primary hyperparathyroidism (90%) including parathyroid cancer in 15% of all affected by HPT-JT, cemento-ossifying fibromas of the maxilla or mandible (30%), bilateral renal cysts (10%), renal hamartoma [highly penetrant in one family (6)], and Wilms tumor (rare). Uterine tumors may also be part of HPT-JT (7). Germline inactivating HRPT2 mutation has also been reported in a minority of kindreds with FIHP without or with parathyroid cancer (2, 8, 9, 10) and in 30% or more of patients with apparently sporadic parathyroid cancer (11, 12).
Several features distinguish the familial parathyroid tumors associated with germline HRPT2 mutation from parathyroid tumors in other familial settings. Among the hereditary syndromes with hyperparathyroidism, HPT-JT stands alone in its high penetrance for parathyroid cancer. Despite this, the parathyroid glands develop tumors asynchronously; sometimes only a single parathyroid tumor is found at surgery. Besides frank malignancy, a high percentage of parathyroid tumors in HPT-JT and HRPT2-associated FIHP are classified as atypical adenomas, indicating histological characteristics usually associated with cancer in other tissues but without the essential criterion of extension beyond the capsule of the parathyroid gland. About 20% of parathyroid tumors in HPT-JT, whether benign or malignant, demonstrate gross or microscopic cysts that would be unusual in other settings (2, 13, 14). Parathyroid cancers in HPT-JT have a high mortality from uncontrollable severe hyperparathyroidism. This cancer has metastasized systemically as early as age 26, making prospective screening and early treatment particularly important in HPT-JT (15).
The proband in the current report presented at age 29 with apparently sporadic primary hyperparathyroidism that was corrected by excision of a hard extrathyroidal nodule classified as an atypical parathyroid adenoma. Because of this pathology, his germline DNA was analyzed and revealed an HRPT2 mutation.
Guarnieri et al. (1) employed multiple modalities in their family-screening strategy. Two rounds of genetic screening identified the same HRPT2 mutation in nine more relatives. With an average age of 34, each had been asymptomatic with regard to HPT-JT. The carriers of the mutated HRPT2 gene were then screened biochemically with serum calcium and PTH and with imaging studies that included jaw pantomography and ultrasonography of the neck and kidneys. No extraparathyroid features of HPT-JT were detected, except possible uterine tumors in two members.
Neck ultrasound in two asymptomatic carriers revealed extrathyroidal nodules that were followed up by fine needle aspiration (FNA) and/or surgery. The proband’s sister was eucalcemic but had modestly elevated PTH; FNA showed very high PTH values, diagnostic of parathyroid tissue, and she underwent en bloc resection of a parathyroid carcinoma. A brother declined FNA and chose surgical excision of his extrathyroidal nodule. His tumor was thyroidal and presumably unrelated to HPT-JT. During prospective screening 12 yr after his initial presentation, the proband was found by ultrasound to have an extrathyroidal nodule contralateral to his earlier parathyroid tumor; he now has normal serum calcium and PTH. FNA revealed a high PTH value in the aspirate, and a second atypical parathyroid adenoma with capsular invasion was excised en bloc. Thus, among nine carriers within one family, neck ultrasound was a critical method for early detection of two initial presentations of parathyroid tumor and one contralateral recurrence; and at least one of the initial presentations was an occult parathyroid cancer.
The issue of early detection of poorly hormone-secreting but potentially malignant endocrine tumors raised in this report (1) underscores important aspects relevant to other endocrine tumors. A central issue for tumor screening is that potentially secretory tumors in any tissue cover a spectrum in grades of hormone secretory activity; at one extreme is the so-called "nonfunctional" tumor, defined as a tumor that may not secrete hormones at all or that may not even synthesize the characteristic hormone(s). This can be illustrated with certain tumors in the multiple endocrine neoplasia (MEN) syndromes.
The foregut-derived carcinoid tumors in MEN1 seldom secrete the peptides and biogenic amines associated with the classic carcinoid syndrome and are thus most frequently first detected by imaging studies. Males with MEN1 are particularly at risk from malignant thymic carcinoid tumors that are usually clinically silent but can often be detected by chest computed tomography (CT) or magnetic resonance imaging (MRI); nevertheless, this risk underlies current policy in most centers of doing prophylactic transcervical thymectomy at the time of initial neck exploration in all patients with MEN1 and hyperparathyroidism. In both sporadic and MEN1-associated cases, the early detection and surveillance of pituitary tumor that does not secrete or even synthesize hormone(s) depends on imaging studies, because they are often clinically silent until they become large enough to cause mass effects. In MEN1, periodic surveillance by pituitary imaging in the absence of suggestive symptoms is standard practice (16). Gastrinomas and insulinomas predominate among the enteropancreatic tumor manifestations of MEN1, but virtually 100% of operated MEN1 patients have additional clinically silent pancreatic tumors that are often not anticipated by preoperative imaging studies. Thus, although periodic abdominal imaging by CT and/or MRI is still recommended in this disease (16), more sensitive techniques, such as endoscopic ultrasound, that allow the earlier preclinical detection of islet cell tumors are being explored (17). Periodic retroperitoneal imaging by CT and/or MRI is also recommended to screen for clinically silent, but potentially malignant, pheochromocytomas in carriers of germline RET or VHL mutations
Guarnieri et al. (1) illustrate the three levels of patient screening that are often available to the endocrinologist in a familial cancer syndrome: 1) carrier ascertainment with a specific gene mutation test in the germline,1 2) tumor surveillance by endocrine testing, and 3) tumor surveillance by imaging. Perhaps the HRPT2 mutation carrier state alone should trigger an aggressive parathyroid intervention, even if the patient is asymptomatic and without evidence of tumor. After all, prophylactic total thyroidectomy to prevent medullary thyroid cancer seems highly effective in young asymptomatic RET mutation carriers in MEN2A kindreds (18). In the case of asymptomatic HRPT2 mutation carriers, there are several arguments against prophylactic parathyroidectomy: the fraction of parathyroid cancers that is curable in HPT-JT under surveillance is not known; the mortality from parathyroid cancer in HPT-JT is uncertain but seems less than 15% of all carriers; accomplishing a total parathyroidectomy may be difficult and carries a risk of recurrent laryngeal nerve damage; lifelong management of the resulting postsurgical hypoparathyroidism may be complex.
Among carriers identified by mutational screening, Guarnieri et al. (1) suggest potential benefit of tumor surveillance by imaging for the early detection of aggressive parathyroid tumors. Does this earlier detection translate into improved patient status, including improved survival? Although we would agree that this is plausible, no large-scale study of this issue is practical. Furthermore, apart from this report, are non- or poorly PTH-secreting parathyroid cancers going to be observed because of improved surveillance in patients and families carrying germline HRPT2 mutation? In general, hormonally nonsecreting parathyroid cancer is quite rare.
What is the status of PTH-related surveillance among HRPT2 mutation carriers (1)? Surveillance for parathyroid tumors with serum calcium measurement alone is the least expensive approach but would miss tumors such as in the carrier with parathyroid cancer showing a modest rise in PTH but normal calcium (1). Adding an immunoradiometric assay for PTH to the calcium blood check would enhance the power of the screen without much added expense or inconvenience. The status of parafibromin expression in a parathyroid tumor, accessible by FNA, might aid in risk assessment. Although sporadic parathyroid adenomas harbor two intact HRPT2 genes (19), the vast majority of parathyroid cancers demonstrate inactivation of both HRPT2 alleles and would therefore be predicted to lack parafibromin expression (8, 11). This has been borne out by immunohistochemical studies of parathyroid tumors (20). Two concerns argue against the use of parafibromin via FNA to analyze suspected parathyroid malignancies. First, FNA of a parathyroid cancer carries the risk of inadvertent tumor seeding along the needle track. Second, even benign parathyroid adenomas from patients with HRPT2 germline mutation fail to express parafibromin (20).
Better approaches to parathyroid tumor surveillance are clearly needed. The study in one large family makes a strong case that neck ultrasound should be considered for surveillance in likely carriers with HRPT2 mutation and reminds us that, with regard to endocrine cancer surveillance, the status quo is rarely good enough (1).
Acknowledgments
This work was supported by the intramural division of the National Institute of Diabetes and Digestive and Kidney Diseases.
Footnotes
Abbreviations: CT, Computed tomography; FIHP, familial isolated hyperparathyroidism; FNA, fine needle aspiration; HPT-JT, hyperparathyroidism-jaw tumor syndrome; MEN, multiple endocrine neoplasia; MRI, magnetic resonance imaging.
1 At present, HRPT2 mutation testing is negative in about half of HPT-JT families with linkage to the HRPT2 locus on 1q25. Linkage of their trait to 1q25 makes it highly likely that that family has an HRPT2 mutation that has been unrecognized (2 ). 
Received June 8, 2006.
Accepted June 20, 2006.
References
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