Review Article

Sandy H. Fang, MD; Geeta Lal, MD, MSc, FRCS(C), FACS

ABSTRACT Objective: To review the current knowledge pertaining to the etiology, molecular pathogenesis, and management of parathyroid carcinoma, a rare presentation of primary hyperparathyroidism. Methods: The existing MEDLINE English-language literature was reviewed using the search terms parathyroid and carcinoma or cancer. Results: Parathyroid cancer is a rare endocrine tumor accounting for a small proportion of cases of primary hyperparathyroidism. Recent database studies indicate increasing incidence rates. Its etiology is unknown, although numerous molecular alterations have been described, and the tumors also occur in association with germline mutations in the CDC73 gene. Most affected patients present with severe hypercalcemia; however, the diagnosis can be challenging. Complete surgical resection remains the mainstay of treatment and provides the best chance of cure, although data from small series suggest that external beam radiation may also reduce the high recurrence rates. No effective chemotherapy regimens are currently available. A significant number of patients develop recurrent disease and need additional procedures; however, long-term survival is possible with palliative surgery. Medical management of chronic and debilitating hypercalcemia with calcimimetics is often necessary and is an important adjunct in patients with recurrent and metastatic disease. Conclusions: Further elucidation of the molecular pathogenesis of parathyroid carcinomas will enhance our understanding of etiology and behavior of this uncommon entity. Future research must be directed at identifying more effective therapies for this condition. (Endocr Pract. 2011; 17[Suppl 1]:36-43) Abbreviation: PHPT = primary hyperparathyroidism INTRODUCTION Primary hyperparathyroidism (PHPT) is a common cause of hypercalcemia in the outpatient setting. Although most parathyroid tumors are benign, a minority of PHPT cases results from parathyroid carcinoma. The debilitating effects of this disease arise from the sequelae of hypercalcemia, which is also usually the first sign of cancer recurrence. This article reviews the incidence, diagnosis, and treatment of parathyroid cancer and also provides a stateof-the-science update on molecular biology and therapies for this rare, but sometimes challenging condition.
Submitted for publication October 2, 2010 Accepted for publication November 30, 2010 From the Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa. Address correspondence and reprint requests to Dr. Geeta Lal, Division of Surgical Oncology and Endocrine Surgery, 200 Hawkins Dr, 4641 JCP, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. E-mail: Geeta-lal@uiowa.edu. Published as a Rapid Electronic Article in Press at http://www. endocrine practice.org on March 29, 2011. DOI:10.4158/EP10310.RA Copyright 2011 AACE.

INCIDENCE Classic textbook teaching indicates that a single parathyroid adenoma accounts for between 85% and 90% of PHPT cases. Multiple-gland disease (multiple adenomas or hyperplasia of all parathyroid glands) occurs in 10% to 15% of cases, while parathyroid carcinomas make up less than 1% of cases. Using the national Surveillance,

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Epidemiology, and End Results database, Lee et al (1) reported incidence rates of parathyroid cancer as less than 1 per million population per year over a 16-year period from 1988 to 2003. In stark contrast to benign parathyroid disease, which is 3 to 4 times more common in women, their study also demonstrated an equal male to female distribution. The authors also noted that during the study time span, the incidence of parathyroid carcinomas increased by 60%, from 3.58 per 10 million population during the 1988 to 1991 period to 5.73 per 10 million population during 2000 to 2003. This increase in incidence may partly reflect the overall increasing use of laboratory screening for hypercalcemia. RISK FACTORS The etiology of parathyroid carcinoma is poorly understood. Rarely, parathyroid carcinoma has been reported in patients with long-standing secondary hyperparathyroidism (1) or those with a history of head and neck irradiation, although the relationship in the latter scenario is less clear than in benign parathyroid disease. In addition, there is also a well-described genetic predisposition. Parathyroid cancer has been associated with a rare autosomal dominant inherited disorder known as hyperparathyroidismjaw tumor syndrome. In this condition, affected persons develop PHPT and ossifying fibromas of the mandible and maxilla and, less commonly, renal lesions such as cysts, hamartomas, or Wilms tumors. Approximately 10% to 15% of affected persons develop parathyroid cancers, which are often cystic. Hyperparathyroidismjaw tumor syndrome is now known to result from germline mutations in the tumor suppressor gene CDC73 (formerly HRPT2), located on chromosome 1 (2). Parathyroid cancer has recently also been reported, albeit rarely, in familial isolated hyperparathyroidism and multiple endocrine neoplasia type 1 and type 2A (3). MOLECULAR BIOLOGY The identification of genetic syndromes outlined above has paved the way to better understand the pathogenesis of parathyroid cancer. Shortly after the identification of germline CDC73 mutations, several investigators demonstrated that somatic mutations of CDC73 are also present in 66% to 100% of sporadic parathyroid carcinomas (4,5). CDC73 encodes the parafibromin protein. Most of the described mutations are nonsense mutations and are predicted to result in loss of parafibromin expression, although mutations in noncoding regulatory regions or gene inactivation by promoter methylation have also been implicated (6). Interestingly, sporadic benign parathyroid adenomas rarely harbor CDC73 mutations, with reported prevalence rates of less than 1%. The exact role of parafibromin expression in parathyroid cancer pathogenesis is not well understood;

however, it has been reported to inhibit cell proliferation (7) and promote apoptosis. Loss of parafibromin expression has been hypothesized to abrogate the inhibitory effect of parafibromin on cyclin D1 activity, thus leading to neoplastic transformation. Other oncogenes and tumor suppressor genes have been linked to parathyroid carcinoma. Studies have shown loss of heterozygosity in the long arm of chromosome 13q, a region containing 2 tumor suppressor genes, RB1 (retinoblastoma, 13q14.3) and BRCA2 (13q12.3) in parathyroid carcinomas. One group reported loss of heterozygosity at the RB1 locus in 100% of carcinomas (11/11 samples), but in only 5% of adenomas (1/19 samples). Immunohistochemical studies showed near-complete or total absence of RB1 expression in 88% of the carcinomas, whereas the adenomas demonstrated normal RB1 staining patterns (8). In contrast, other investigators did not detect any point mutations, microdeletions, or insertions in either RB1 or BRCA2, suggesting that the gene expression may be epigenetically regulated or that other tumor suppressors in this region may be important in parathyroid carcinogenesis (9). In general, parathyroid carcinomas have significantly higher fractional allelic losses at various loci compared with losses in benign parathyroid tumors (32% vs 14%, P = .03) (10). Other regions associated with loss of heterozygosity linked to parathyroid cancer include PTEN, HRAS, MET, and TP53 (11). The CCND1 (previously known as PRAD1 [parathyroid adenomatosis 1]) oncogene was discovered during the molecular characterization of several large sporadic parathyroid adenomas harboring DNA rearrangements that involved the PTH gene locus on chromosome 11. CCND1 is overexpressed in more than 90% of parathyroid carcinomas (12); however, its exact role in the pathogenesis of parathyroid carcinomas remains to be determined. A recent study also showed loss of APC (adenomatous polyposis coli) expression via hypermethylation of its promoter in 5 of 5 parathyroid carcinomas. This was accompanied by accumulation of stabilized active nonphosphorylated b-catenin. Taken together, these findings strongly suggest aberrant activation of the WNT/bcatenin signaling pathway in these tumors (13). CLINICAL PRESENTATION The classic symptoms of PHPT include stones, bones, abdominal groans, and psychiatric overtones. As opposed to their counterparts with benign disease, patients with parathyroid cancer are severely symptomatic at presentation, with most of the clinical manifestations resulting from severe hypercalcemia. These include severe nephrolithiasis, nephrocalcinosis, and impaired renal function in up to 80% of affected persons and severe bone involvement in up to 90%. The latter may include osteitis fibrosa cystica, diffuse osteopenia, or pathologic fractures from extreme osteoporosis. Other constitutional symptoms associated

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with PHPT such as fatigue, loss of concentration, malaise, bone pain, polydipsia, polyuria, and depression may also be present. Recurrent severe pancreatitis and peptic ulcer disease are common. In addition to these stigmata of parathyroid disease, a palpable neck mass can be present in 30% to 75% of patients with parathyroid carcinoma, a finding that is quite rare in benign disease (14-16). More recent series, however, indicate that this number may be lower. Kleinpeter et al (17) noted a palpable mass in only 22% of their patients preoperatively. Hoarseness, resulting from recurrent laryngeal nerve palsy, and palpable, enlarged lymph nodes can also provide a clue to the presence of a carcinoma. When patients develop marked hyperparathyroidism, they may progress to hypercalcemic crisis. This condition presents with anorexia, nausea, vomiting, constipation, acute pancreatitis, shortened QT interval, apathy, drowsiness, and coma, and, if left untreated, it can lead to death. DIAGNOSIS Laboratory Studies Although there are no pathognomonic laboratory features, parathyroid carcinoma should be suspected in the presence of markedly elevated parathyroid hormone levels (>5 times the upper limit of normal) and serum calcium concentrations (usually more than 14 to 15 mg/dL) (16). With more routine laboratory studies being performed, less severe hypercalcemia may be seen in patients with parathyroid carcinoma. In a large, recent series, Busaidy et al (18) reported severe hypercalcemia (>13.5 mg/dL) in only 44% of their patients. In fact, 28% of their patients had mild hypercalcemia (<12 mg/dL), which is more consistent with the presentation of patients with benign disease. Alkaline phosphatase levels are also typically higher in patients with carcinoma when compared with those found in benign parathyroid disease. Elevated serum and urinary human chorionic gonadotropin levels (particularly the hyperglycosylated isoform) have also been reported in patients with parathyroid carcinomas and may have value as diagnostic and prognostic adjuncts (19). A subset of parathyroid cancers also overproduce the N-terminal form of parathyroid hormone; however, the clinical implications of this finding need further study (20). Imaging Studies The studies used for localization of hypercellular parathyroid glands in benign parathyroid disease are also helpful in imaging parathyroid cancers and include ultrasonography, sestamibi scan, computed tomography, and magnetic resonance imaging. Technetium Tc 99m sestamibi is a radionuclide with a high affinity for the mitochondria of parathyroid tissue and is the localization method most commonly used for PHPT (Fig. 1). Although there are no particular features that distinguish benign from malignant

Fig. 1. Sestamibi scan showing delayed and persistent uptake in the left neck (arrow), consistent with a parathyroid tumor on the left side. There are no specific features to suggest malignancy. This patient had a partially intrathyroidal parathyroid carcinoma at resection.

tumors on these scans, they are nevertheless useful to detect sites of recurrent or metastatic disease. On ultrasonography, parathyroid carcinomas may have ill-defined margins and possible signs of invasion (21). Invasion into surrounding structures, as well as lymph node metastases, may be seen. Ultrasonography may additionally be useful to guide fine-needle aspiration biopsy of suspected lymph node metastases. However, fine-needle aspiration biopsy of the primary tumor is contraindicated when parathyroid carcinoma is suspected because of the risk of needle-track seeding and tumor dissemination. Computed tomography and magnetic resonance imaging have been variably used to localize parathyroid tumors, although 4D-computed tomography is being increasingly used at some centers, particularly for recurrent or persistent disease or in patients suspected of having multiglandular disease (22,23). The latter may have the advantage of providing functional (based on alterations in perfusion characteristics) and anatomic information (24). Invasive studies such as selective venous catheterization may also be used to localize lesions when noninvasive studies have been noncontributory. Once parathyroid cancer is diagnosed, staging studies are not necessarily needed. However, if there are symptoms suggestive of metastatic disease or if calcium and parathyroid hormone levels remain elevated, computed tomography and magnetic resonance imaging are very helpful for the detection and characterization of metastatic lesions. More recently, positron emission tomography has also shown utility for the detection of metastatic parathyroid cancers (25). An important caveat in this scenario is that brown tumors can be fluorodeoxyglucose-avid on this imaging and may be mistaken for metastases (26).

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Pathology At the time of operation, the diagnosis of parathyroid carcinoma primarily relies on clinical suspicion, as frozen section is unreliable. Several characteristics may be helpful. Parathyroid carcinomas typically tend to be larger than benign tumors, with reported median sizes of 3.3 cm for carcinomas and 1.5 cm for adenomas (27,28). Parathyroid carcinomas also tend to be more firm, irregularly shaped, and have a whitish-gray color, and they are often adherent to or may invade surrounding neck structures. Typical parathyroid cancers are characterized by chief cells (which are almost always the predominant cell type) arranged in a trabecular, solid, or acinar pattern with the loss of the typical lobular pattern (Fig. 2A). Schantz and Castleman, in a classic article from 1973 on the pathology of parathyroid carcinoma, identified the major criteria for the diagnosis of parathyroid malignancy: capsular or vascular invasion (present in 67% and 12% of their cases, respectively), fibrous trabeculae (present 60% of cases), and numerous mitotic figures (present in 80% of cases) (29). It is important to note that classic histologic findings described above are not present as frequently as initially reported. One recent study reported that fibrous bands, mitoses, and vascular invasion were observed individually in only 37% of patients (30). Furthermore, many of these features, including adherence to surrounding structures, fibrous bands, trabecular growth, and mitoses, can also be found in benign lesions (31,32). Benign adenomas may also have areas of pseudoinvasion (entrapment of tumor cells in the capsule of adenomas that have undergone cystic degeneration), rather than true capsular invasion, which is characterized by a tongue-like protrusion of the cells (Fig. 2B) through the collagenous capsule. Vascular invasion is defined by the presence of affected vessels within the tumor capsule or surrounding soft tissues, which is in contrast to artifactual dislodgement of tumor cells, which are

seen as clusters of cells that are not surrounded by endothelium or associated with thrombus. While some authors consider vascular invasion virtually pathognomonic of carcinoma (33), some debate still exists as to the overall diagnostic value of both vascular and capsular invasion (34). Carcinomas can also invade surrounding structures, such as the thyroid gland, esophagus, trachea, strap muscles, and recurrent laryngeal nerve. The term atypical adenoma or adenoma with suspicious features is used to describe tumors that share some of the features of carcinomas, but which lack definitive evidence of invasive growth. The long-term outcomes of these tumors must be better defined. It is important to distinguish a recurrent parathyroid tumor from parathyromatosis, which can result from incomplete excision or capsular disruption during resection of a benign adenoma. Immunohistochemical staining for cell-cycle associated antigens (such as Ki-67 and cyclin D1) is helpful in distinguishing parathyroid carcinomas from parathyroid adenomas; however, the presence of overlap limits its clinical utility. Other studies report that evaluation for loss of heterozygosity or mutations in the CCND1 gene and loss of parafibromin by immunohistochemistry may be useful adjuncts in diagnosing parathyroid carcinomas (35). More recently, microRNA profiling studies suggest that differential expression of these molecules (particularly mir-126) may also have utility in this regard (36). MANAGEMENT Surgery The only curative treatment for parathyroid cancer is surgical resection. If parathyroid cancer is suspected preoperatively, obtaining anatomic imaging such as computed tomography is prudent to define the extent of disease and to plan the surgical approach. However, all too commonly

Fig. 2. Microscopic appearance of parathyroid carcinoma. Panel A, Solid proliferation of chief cells at high power (hematoxylin and eosin stain; original magnification 400). Panel B, A tongue of parathyroid carcinoma invading surrounding soft tissues (hematoxylin and eosin stain; original magnification 100).

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the diagnosis is made intraoperatively, and occasionally, postoperatively. As described previously, the intraoperative identification of a large, firm, white-graycolored tumor with infiltration of surrounding structures should alert the surgeon to a possible carcinoma. Analysis of the Surveillance, Epidemiology, and End Results database by Lee et al (1) revealed that most parathyroid cancers (78.6%) were resected by simple parathyroidectomy, whereas only 12.5% of patients underwent en bloc resection. These data highlight the difficulty in discerning benign from malignant parathyroid tissue during surgical resection. Incomplete excisions are associated with very high recurrence rates. Therefore, en bloc resection at the time of initial operation is the criterion standard and provides the best chance for cure and long-term survival. En bloc resection entails parathyroidectomy with ipsilateral thyroid lobectomy and removal of contiguous lymph nodes (tracheoesophageal, paratracheal and upper mediastinal) from the ipsilateral central neck. Any adherent adjacent structures such as the strap muscles and other soft tissues must also be resected. The recurrent laryngeal nerve is not typically sacrificed unless there is direct tumor involvement. A modified radical neck dissection is performed in case of lateral compartment nodal metastases. Prophylactic lateral neck dissection is not recommended. In cases where parathyroid carcinoma is identified at final pathologic examination, repeated surgery with excision of the ipsilateral thyroid lobe, contiguous structures and lymph nodes may be considered if the features are typical or the patient remains hypercalcemic and pathologic findings confirm extensive vascular or capsular invasion. Patients with equivocal pathologic findings and normocalcemia may be monitored closely, rather than undergo reoperation. In patients with hyperparathyroidismjaw tumor syndrome, surgery should be aimed at identifying all parathyroid glands with en bloc removal of any abnormal tissue. Prophylactic parathyroidectomy is not recommended because of the incomplete penetrance of parathyroid cancers in these patients (37). Surgery is also the mainstay of therapy for recurrent or metastatic parathyroid cancer, if it is resectable. Parathyroid cancers metastasize via the lymphatic and hematogenous routes with lung, bone, and liver being the most common distant metastatic sites. Multiple operations may be needed. Although rarely curative, surgery and consequent reduction of tumor burden will often render patients normocalcemic for some duration, or at least make their hypercalcemia more amenable to medical management. Chemotherapy and Biotherapy Chemotherapy with dacarbazine alone or in combination with other agents, such as 5-fluorouracil and cyclophosphamide has been reported to provide partial biochemical and pathologic (tumor necrosis) responses for up to 5 months in various case reports of patients with metastatic

functional parathyroid carcinoma (38,39). Another case report noted a complete resolution of metastatic nonfunctional parathyroid carcinoma after 18 months of treatment with methotrexate, adriamycin, cyclophosphamide, and lomustine (CCNU) (40). Other agents such as vincristine and doxorubicin have been used in a larger number of patients; however, they have also not been effective (15). Therefore, chemotherapy currently has a limited role in the care of patients with parathyroid carcinoma. However, it may be used in patients with metastatic disease and hypercalcemia refractory to other therapies. Other approaches include antiparathyroid hormone immunotherapy (41) and octreotide to reduce parathyroid hormone secretion, the latter showing promising results in 2 cases of metastatic parathyroid cancer (42). In vitro studies show that the telomerase inhibitor azidothymidine also inhibits the proliferation of cultured parathyroid carcinoma cells (43) and may be a potential therapeutic agent in this malignancy. Additional clinical studies are clearly needed to better define the roles of chemotherapy and other agents in the treatment of this parathyroid cancer. Radiation Therapy In the last 10 years, several centers have shown a decrease in local recurrence rates and even improved survival after external beam radiation therapy. In the largest series from the MD Anderson Cancer Center (18), 6 of 18 patients with the diagnosis of locally invasive disease (defined as microscopic or macroscopic disease extension outside the parathyroid gland involving adjacent tissues) received adjuvant radiation therapy (dosage range between 50 and 63 Gy) within 2 months after initial surgery. Only 1 of 6 patients treated with adjuvant radiation developed recurrent disease compared with 5 of 12 patients who did not receive radiation treatment. Overall, the authors noted that 5 of 8 patients with localized tumors had recurrence compared with 6 of 18 with locally invasive disease, suggesting that radiation may decrease local relapse rates. In the series from the Mayo Clinic (44), 4 of 61 patients underwent adjuvant radiation therapy because of concerns about microscopic or subclinical residual disease. None of these patients had experienced recurrence at 53 to 67 months of follow-up. At the Princess Margaret Hospital in Toronto, Chow et al (45) also treated 6 patients with adjuvant radiation therapy for microscopic residual disease, defined as patients in whom there was evidence of disease at or within 2 mm of the resection margin or in whom the tumor was shaved off adjacent structures in the neck. None of these patients had developed a recurrence at a mean follow-up of 62.3 months. Although promising, definitive conclusions regarding the role of adjuvant radiation are limited by the small sample sizes and retrospective nature of these series. Large-scale prospective studies are unlikely to be completed because this disease is so rare; however, adjuvant

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radiation therapy should be considered in patients at high risk of local relapse (close or positive margins, extension into surrounding soft tissue or other structures, rupture of capsule). In the absence of clear guidelines, treatment decisions in this regard must continue to be personalized in a multidisciplinary setting. Radiation therapy is also useful to treat unresectable, recurrent neck disease or to palliate bone metastases. Medical Management Patients with parathyroid carcinoma may present with hypercalcemic crisis, either at initial presentation or in the setting of widespread metastases. There are 4 basic treatment goals in these patients: (a) correct dehydration, (b) enhance renal excretion of calcium, (c) inhibit accelerated bone resorption, and (d) treat the underlying disorder. Initial treatment involves aggressive fluid resuscitation with normal saline. Once fluid status is corrected, a loop diuretic, such as furosemide may be given to increase renal excretion of calcium. Thiazide diuretics are contraindicated because they enhance distal tubular absorption of calcium. If the patient remains hypercalcemic, then intravenous bisphosphonates, such as pamidronate and zoledronate, may be used. These medications must be used with caution because they have been associated with acute renal failure and rare reports of avascular jaw necrosis. Bisphosphonates have a slower onset of action and may be used in conjunction with calcitonin, which has a rapid onset of action. Corticosteroids may also lower serum calcium levels by increasing urinary calcium excretion and decreasing intestinal calcium absorption. Plicamycin is effective, but like calcitonin, its response is transient. Cinacalcet (brand name Sensipar, Amgen, Thousand Oaks, California) is a calcimimetic agent, which binds to calcium-sensing receptors on the surface of parathyroid cells, increasing the receptors sensitivity to extracellular calcium and decreasing the secretion of parathyroid hormone. Cinacalcet has been shown to be effective in controlling hypercalcemia in patients with inoperable parathyroid cancer in a multicenter study (46). The dosages in this study were titrated from 30 mg twice daily up to 90 mg 4 times daily, as needed, to lower calcium levels. The drug was reasonably well tolerated and gastrointestinal symptoms were the most frequently reported adverse events. Cinacalcet can also be used in patients with renal failure and it has therefore become an important treatment option for patients with intractable hypercalcemia and inoperable disease. Of note, the decline in calcium levels is more sustained than the drugs effects on parathyroid hormone levels; the reasons for this discrepancy remain unclear. PROGNOSIS Parathyroid carcinomas are associated with an indolent, slowly progressive course. Patient follow-up is critical

and is recommended at 4- to 6-month intervals. Follow-up should include physical examination, along with measurements of calcium and parathyroid hormone levels. Serial elevations of parathyroid hormone are highly suggestive of recurrent disease. The initial sign of relapse is often an episode of escalated hypercalcemia, which can be debilitating. Most patients with parathyroid carcinoma succumb to the effects of uncontrolled hypercalcemia (hypercalcemic crisis) rather than metastatic tumor burden (16,33). Once recurrence is noted, the imaging studies discussed earlier are needed to localize the lesions, assess sites of spread, and determine resectability. Local recurrence occurs at regional lymph nodes in 30% of cases, while distant metastases most frequently involve the lungs, liver, and bone. Reported tumor recurrence rates in the literature vary between 22% and 60% after surgery (17,18,47,48) with en bloc resection having lower recurrence rates (47). Despite recurrences, prolonged survival is possible with aggressive resection and medical management. Reported 10-year survival rates vary from 49.1% in the National Cancer Database Survey (28) to 70% in the Swedish Cancer Registry Database (48). A more recent review of cases from the Surveillance Epidemiology and End Results database reported overall 10-year survival rates of 67.8% (1). A number of studies have examined various clinical and histopathologic features as predictors of prognosis and failed to identify any relationship with tumor size, lymph node status (28), vascular invasion, or presence of mitoses (29). In a review of 358 published cases, Koea and Shaw (49) reported higher local recurrence rates for patients treated with simple parathyroidectomy on both univariate (P<.0001) and multivariate analysis (P<.007). Factors associated with higher mortality rates included those patients treated initially with simple parathyroidectomy, lymph node or distant metastases at presentation, and nonfunctioning tumors. A recent analysis of 330 reported cases in the literature excluded nonfunctioning tumors and identified male sex, higher calcium levels, and younger age as adverse clinical prognostic factors (50). In this series, presence of vascular invasion, fibrous bands, and lymph node metastases were also associated with higher overall recurrence and death rates. The design of the study precluded multivariate analyses, but underscored the need to develop a hitherto unavailable clinical and pathologic staging system similar to the TNM classification of other tumors. NONFUNCTIONAL PARATHYROID CANCER A rare variant of parathyroid cancer manifests with an absence of hyperparathyroidism. The typical symptom is an expanding neck mass that presents late in the course of the disease. Only 19 cases have been reported in the literature thus far (51). Treatment is similar to functional tumors

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(complete resection); however, early recurrence is difficult to detect because there is no serum marker to follow. CONCLUSION Parathyroid cancer is a rare entity and often presents with the debilitating effects of hypercalcemia, although rarely these tumors may be nonfunctional. Diagnosis can be challenging, and further studies into the molecular pathogenesis of these tumors will help in this regard. En bloc surgical resection remains the mainstay of treatment and provides the best chance of cure, although data from small series suggest that external beam radiation may help reduce the high recurrence rates. Long-term survival is possible with palliative surgery, and cinacalcet is an important adjunct to control hypercalcemia associated with recurrent and metastatic disease. Future research should be directed at identifying more effective therapies for this disease. ACKNOWLEDGMENT The authors would like to thank Dr. Robert A. Robinson (Department of Pathology) for assistance with the preparation of the figures. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES
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