Parathyroid cancer should also be considered in any hypercalcemic patient without a history of prior neck surgery who presents with recurrent laryngeal nerve palsy.
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Immunohistochemistry is used to improve the accuracy of the diagnosis of parathyroid carcinoma. One approach has involved the use of proliferation markers. Increased labeling of cell cycle—associated antigens Ki, cyclin D1 has been shown in parathyroid carcinoma compared with adenoma, 66 , 68 but overlap among these tumor types has limited the utility of this approach.
Decreased expression of p27, an inhibitor of cyclin-dependent kinase, and abnormal galectin-3 expression have been shown in carcinomas. The association between these abnormalities and high Ki labeling has been suggested to increase the likelihood of malignancy. Evaluation of HRPT2 gene abnormalities seems to be a more promising diagnostic tool. To date, limited data are available in equivocal cases, where this technique would have the greatest diagnostic utility Table 3. It is important to emphasize that the diagnostic potential of these tests hinges on their common presence in parathyroid cancer and their rarity in benign disease.
Because benign parathyroid disease is so much more common than parathyroid cancer, a test that has a detectable detection rate in benign parathyroid disease even if low would have limited clinical utility. The combined findings of negative parafibromin staining and HRPT2 gene abnormalities increase the likelihood of a malignancy.
Immunohistochemical analysis of parafibromin expression. Top Normal parathyroid. Middle Parathyroid adenoma. Bottom Parathyroid carcinoma. Parathyroid carcinoma typically runs an indolent, albeit progressive, course because the tumor has a rather low malignant potential.
Rarely, distant metastases occur in bone, pleura, pericardium, and pancreas. The identification of HRPT2 mutations in eight patients with apparently sporadic parathyroid cancers as germline events 36 , 37 , 45 , 46 suggests that a subset of these patients might have HPT-JT syndrome or variant thereof. This observation has implications for the management of recurrent disease in parathyroid cancer. When a patient develops a recurrence of parathyroid cancer, in addition to the likelihood that the original carcinoma has progressed, a new tumor should be carefully sought, because additional, discrete parathyroid tumors can develop in patients with HPT-JT syndrome.
Surveillance for renal and jaw lesions is also indicated. Moreover, the relatives of a patient with seemingly sporadic parathyroid carcinoma carrying a germline HRPT2 mutation are susceptible to the development of parathyroid cancer or other manifestations of HPT-JT syndrome. As suggested by Kelly et al. A metal-clip marking the glands left in situ may also be considered, anticipating the need for future surgery. Because of parathyroid cancer in this setting has incomplete penetrance i. In those who do undergo complete parathyroidectomy, autotransplantation of parathyroid tissue to the forearm is not recommended to avoid the introduction of potentially malignant tissue at an ectopic site.
Surgery is the only curative treatment for parathyroid carcinoma and consists of complete resection of the primary lesion at the time of initial operation.
Patients who present with features suggestive of parathyroid carcinoma warrant thorough exploration of all four parathyroid glands, because parathyroid carcinoma has been reported to coexist along with benign adenomas or hyperplasia. When the diagnosis of parathyroid cancer is made after parathyroid surgery on the basis of pathology, as often happens, the management plan becomes more complex.
If the macroscopic characteristics of the tumor are typical of a parathyroid carcinoma, and the pathology shows extensive vascular or capsular invasion or if hypercalcemia persists, further exploration of the neck can be considered after appropriate localization studies see below. The structures surrounding the tumor should be excised as described above. When telling histologic features are absent, the patient is normocalcemic and the diagnosis is only based on equivocal pathology, immediate reoperation is not indicated, because the simple complete resection of the tumor may turn out to be curative.
However, such patients should be monitored closely with regular measurement of serum calcium and PTH levels. Most recurrences occur 2—3 yr after the initial operation, but this period is variable, and a prolonged disease-free interval of as long as 20 yr has been reported. Fine-needle aspiration of a suspicious lesion with measurement of PTH in the eluate should be used with caution, if at all, to avoid seeding the needle track with deposits of malignant cells. The management of recurrent or metastatic parathyroid carcinoma is primarily surgical.
Accessible distant metastases, particularly in the presence of localized metastatic disease, should also be excised, if possible. Although resection of single metastasis or other foci of malignant tissue is rarely curative, their removal may result in periods of normocalcemia ranging from months to years. Chemotherapy generally is disappointing. Several regimens have been attempted nitrogen mustard, vincristine, cyclophosphamide, and actinomycin D, and adriamycin alone or in combination with cyclophosphamide and 5-fluorouracil , but none of them has proved to be effective.
With the exception of a single report 91 of an apparent cure 10 yr in a patient with tumor invasion of trachea, radiation therapy has little, if any, effect in invasive parathyroid cancer. The Mayo Clinic reported a disease-free survival at a median follow-up period of 60 mo in four patients who received postoperative adjuvant radiotherapy.
When parathyroid carcinoma has became widely metastatic and surgical options are exhausted, clinical management becomes a matter of controlling the hypercalcemia.
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Potent intravenous bisphosphonates pamidronate and zoledronate may transiently control hypercalcemia, but patients frequently become refractory to them. Plicamicin is effective, but the response is transient, and repeated courses may be associated with toxicity. Octreotide, the long-acting somatostatin analog, has been reported to inhibit PTH secretion in two cases of metastatic parathyroid carcinoma.
Anti-PTH immunotherapy showed promise in two recent case reports. Another approach is to target the parathyroid calcium-sensing receptor CaSR. Calcimimetics, allosteric modulators of the CaSR, directly reduce parathyroid cell hormone secretion by binding to sites that increase the receptors' affinity for calcium.
A first-generation calcimimetic, R, was used for 2 yr in a patient with metastatic parathyroid cancer with controlled hypercalcemia. Recently, the results of a multicenter study of cinacalcet in 29 patients with inoperable parathyroid carcinoma were published.
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Secondary endpoints included changes from baseline in serum calcium, plasma PTH, bone turnover markers, and health-related quality of life variables. The dose of cinacalcet in this study was titrated from 30 mg twice daily a dose that might be effective in benign PHPT up to 90 mg four times daily as required to lower serum calcium levels. Cinacalcet effectively reduced hypercalcemia in about two thirds of patients with inoperable parathyroid carcinoma Fig.
In the responders 18 of 29 patients , serum calcium levels declined from It was of interest that the marked reductions in serum calcium were not accompanied by a similar fall in circulating PTH.
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PTH levels reached a nadir 4 h after drug administration, but the decline was not pronounced, nor was it sustained. Although hypotheses abound, the reason for the discrepancy in calcium and PTH response to cinacalcet remains unclear at this time. Nausea and vomiting were the most common adverse events.
Reported in more than one half of all patients receiving cinacalcet at these doses, these symptoms necessitated discontinuation of drug in some cases. Serious adverse events, including fracture and death, were not considered to be drug related. Instead, they were expected consequences of the patients' longstanding, often widely metastatic, underlying disease. There are no data suggesting that cinacalcet alters the course of the parathyroid cancer itself.
Therefore, this agent should not be introduced to control hypercalcemia in a patient with a metastatic lesion that is accessible and amenable to surgical extirpation.
Furthermore, unlike other options for treatment of hypercalcemia, this agent can be used in patients with the renal impairment so common in patients with longstanding parathyroid cancer. Cinacalcet therefore represents an important new option for management of intractable hypercalcemia in patients with inoperable disease. Reduction in serum calcium concentration in parathyroid cancer with cincalcet. Subjects were given cinacalcet in increasing doses, up to 90 mg four times daily, during the titration phase.
The average serum calcium fell from The prognosis of parathyroid carcinoma is quite variable. No single characteristic correlates with outcome. The best prognosis depends on early recognition and complete excision of the tumor at initial surgery. The mean time to recurrence is usually 3 yr, although intervals of up to 20 yr have been reported. The best opportunity to cure parathyroid carcinoma is to diagnose it before or at the time of parathyroid surgery and for the tumor to be completely removed at the time of the initial operation.
Because the diagnosis is often not clear at the time of presentation, recent attempts to distinguish between benign and malignant disease both by genetic and immunohistological analyses are promising.
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