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Review Article

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