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Review Article

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

Submitted for publication October 2, 2010Accepted for publication November 30, 2010From 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. endocrinepractice.org on March 29, 2011. DOI:10.4158/EP10310.RACopyright © 2011 AACE.

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 “parathy-roid” and “carcinoma” or “cancer.” Results: Parathyroid cancer is a rare endocrine tumor accounting for a small proportion of cases of primary hyper-parathyroidism. Recent database studies indicate increas-ing incidence rates. Its etiology is unknown, although numerous molecular alterations have been described, and the tumors also occur in association with germline muta-tions 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 sur-vival is possible with palliative surgery. Medical manage-ment of chronic and debilitating hypercalcemia with calci-mimetics 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 uncom-mon 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 hypercal-cemia, which is also usually the first sign of cancer recur-rence. This article reviews the incidence, diagnosis, and treatment of parathyroid cancer and also provides a state-of-the-science update on molecular biology and therapies for this rare, but sometimes challenging condition.

INCIDENCE

Classic textbook teaching indicates that a single para-thyroid 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 dis-tribution. 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 dur-ing 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 under-stood. Rarely, parathyroid carcinoma has been reported in patients with long-standing secondary hyperparathyroid-ism (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 hyperparathyroidism–jaw tumor syndrome. In this condition, affected persons develop PHPT and ossify-ing fibromas of the mandible and maxilla and, less com-monly, renal lesions such as cysts, hamartomas, or Wilms tumors. Approximately 10% to 15% of affected persons develop parathyroid cancers, which are often cystic. Hyperparathyroidism–jaw 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 germ-line 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 muta-tions 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 expres-sion 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 para-thyroid carcinomas. One group reported loss of hetero-zygosity 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 het-erozygosity 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 hypermethyl-ation of its promoter in 5 of 5 parathyroid carcinomas. This was accompanied by accumulation of stabilized active nonphosphorylated b-catenin. Taken together, these find-ings strongly suggest aberrant activation of the WNT/b-catenin 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 pre-sentation, with most of the clinical manifestations resulting from severe hypercalcemia. These include severe nephroli-thiasis, 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 para-thyroid disease, a palpable neck mass can be present in 30% to 75% of patients with parathyroid carcinoma, a find-ing 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 hyperparathy-roidism, they may progress to hypercalcemic crisis. This condition presents with anorexia, nausea, vomiting, con-stipation, 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 fea-tures, 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 para-thyroid 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 consis-tent 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 uri-nary 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 ultraso-nography, sestamibi scan, computed tomography, and mag-netic 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

tumors on these scans, they are nevertheless useful to detect sites of recurrent or metastatic disease. On ultra-sonography, 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 selec-tive venous catheterization may also be used to localize lesions when noninvasive studies have been noncontribu-tory. Once parathyroid cancer is diagnosed, staging studies are not necessarily needed. However, if there are symp-toms 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 parathy-roid 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).

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.

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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 help-ful. 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 pathol-ogy 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 con-trast to artifactual dislodgement of tumor cells, which are

seen as clusters of cells that are not surrounded by endo-thelium or associated with thrombus. While some authors consider vascular invasion virtually pathognomonic of car-cinoma (33), some debate still exists as to the overall diag-nostic 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 suspi-cious features” is used to describe tumors that share some of the features of carcinomas, but which lack definitive evi-dence 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 dis-ruption during resection of a benign adenoma. Immunohistochemical staining for cell-cycle associ-ated antigens (such as Ki-67 and cyclin D1) is helpful in distinguishing parathyroid carcinomas from parathyroid adenomas; however, the presence of overlap limits its clin-ical 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 differ-ential 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 pre-operatively, 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).

A B

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the diagnosis is made intraoperatively, and occasionally, postoperatively. As described previously, the intraop-erative identification of a large, firm, white-gray–colored 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 opera-tion 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 radi-cal neck dissection is performed in case of lateral compart-ment nodal metastases. Prophylactic lateral neck dissection is not recommended. In cases where parathyroid carcinoma is identified at final pathologic examination, repeated surgery with exci-sion of the ipsilateral thyroid lobe, contiguous structures and lymph nodes may be considered if the features are typ-ical or the patient remains hypercalcemic and pathologic findings confirm extensive vascular or capsular invasion. Patients with equivocal pathologic findings and normocal-cemia may be monitored closely, rather than undergo reop-eration. In patients with hyperparathyroidism–jaw tumor syndrome, surgery should be aimed at identifying all para-thyroid glands with en bloc removal of any abnormal tis-sue. Prophylactic parathyroidectomy is not recommended because of the incomplete penetrance of parathyroid can-cers 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 com-mon distant metastatic sites. Multiple operations may be needed. Although rarely curative, surgery and consequent reduction of tumor burden will often render patients nor-mocalcemic for some duration, or at least make their hypercalcemia more amenable to medical management.

Chemotherapy and Biotherapy Chemotherapy with dacarbazine alone or in combina-tion with other agents, such as 5-fluorouracil and cyclo-phosphamide has been reported to provide partial biochem-ical 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 nonfunc-tional 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 hyper-calcemia refractory to other therapies. Other approaches include anti–parathyroid 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 stud-ies 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 sur-vival 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, sug-gesting that radiation may decrease local relapse rates. In the series from the Mayo Clinic (44), 4 of 61 patients under-went 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 radia-tion 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 regard-ing 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 com-pleted 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 treat-ment goals in these patients: (a) correct dehydration, (b) enhance renal excretion of calcium, (c) inhibit acceler-ated bone resorption, and (d) treat the underlying disor-der. Initial treatment involves aggressive fluid resuscita-tion 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 contra-indicated 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 cal-cium 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 receptor’s sensitivity to extracellular calcium and decreasing the secretion of parathyroid hor-mone. Cinacalcet has been shown to be effective in con-trolling hypercalcemia in patients with inoperable parathy-roid 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 symp-toms 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 sus-tained than the drug’s effects on parathyroid hormone lev-els; the reasons for this discrepancy remain unclear.

PROGNOSIS

Parathyroid carcinomas are associated with an indo-lent, 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 measure-ments 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 epi-sode of escalated hypercalcemia, which can be debilitat-ing. 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 recur-rence 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, pro-longed 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 parathyroid-ectomy, lymph node or distant metastases at presenta-tion, 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 under-scored the need to develop a hitherto unavailable clinical and pathologic staging system similar to the TNM clas-sification 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 litera-ture 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 pos-sible 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.

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