Parathyroid Carcinoma

Parathyroid carcinoma is a rare endocrine malignancy. It accounts for <1% of cases of sporadic primary hyperparathyroidism (PHPT) and is usually associated with more severe clinical manifestations than its much more common benign counterpart, parathyroid adenoma.1-3 Its course is typically indolent but progressive. The diagnosis of malignancy is often made only when local recurrence or metastases occur, because the histology of parathyroid tumors can be equivocal or frankly misleading.4 Most patients with recurrent disease ultimately succumb to the effects of hypercalcemia rather than to direct tumor invasion or distant metastases. A complete resection of all malignant tissue at the time of initial surgery allows for the greatest likelihood of a cure. Clinical clues to the possibility of a parathyroid cancer, therefore, should lead the surgeon to an aggressive initial operative approach. In the last decade, greater knowledge of the molecular pathogenesis of parathyroid carcinoma has led to the development of diagnostic markers that show promise, particularly when the histology is ambiguous.2, 3 Moreover, there is hope that greater understanding of the pathogenesis of parathyroid cancer will lead to the development of new therapeutic strategies for advanced, inoperable disease. This review focuses on the more recent advances in parathyroid carcinoma, particularly its molecular pathogenesis, diagnosis, and management. To date, >400 cases of parathyroid carcinoma have been reported.5 It is usually a sporadic disease, but familial cases have been described. The largest series comes from the National Cancer database.6 In most series of PHPT, parathyroid carcinoma accounts for <1% of all cases, but an incidence as high as 5% has been reported.1, 7, 8 The use of varying criteria for its pathologic diagnosis is most likely the reason why later studies have shown higher incidence rates. In contrast to benign parathyroid disease, where women predominate over men by a ratio of 3–4:1, parathyroid cancer occurs with equal frequency in both sexes. The age at diagnosis is 10 yr earlier than the typical age when the benign form of PHPT presents (mid-40s versus mid-50s). The etiology of parathyroid carcinoma is largely unknown. A potential role for prior neck irradiation is less clear than in the development of benign parathyroid disease.9-13 Rarely, parathyroid carcinoma has been reported in patients with longstanding secondary hyperparathyroidism.14, 15 In the few such cases, it is unclear whether the currently accepted pathological criteria of parathyroid malignancy were met. Parathyroid carcinoma has also been reported in hereditary syndromes of hyperparathyroidism,16-19 particularly in hyperparathyroidism-jaw tumor (HPT-JT) syndrome,20 a rare autosomal disorder, in which as many as 15% of patients will have malignant parathyroid disease. Because cystic changes are common, this disorder has also been referred to as cystic parathyroid adenomatosis.21 In HPT-JT, ossifying fibromas of the maxilla and mandible are seen in 30% of cases. Less commonly, kidney lesions, including cysts, polycystic disease, hamartomas, or Wilm's tumors, can be present.22 Parathyroid carcinoma has also been reported in familial isolated hyperparathyroidism.17, 23 Recently, parathyroid carcinoma, as defined pathologically, has been reported in multiple endocrine neoplasia type 1 (MEN1) syndrome and with somatic MEN1 mutations.24-26 However, recurrent parathyroid disease in MEN1 may mimic, but not actually be caused by, malignancy. Only one case of parathyroid carcinoma has been reported in the MEN2A syndrome.27 Oncogenes and tumor suppressor genes have been linked to parathyroid carcinomas, especially those involved in the control of the cell cycle. Examples include retinoblastoma (Rb), p53, breast carcinoma susceptibility (BRCA2), and cyclin Dl/parathyroid adenomatosis gene 1 (PRAD1) genes.28, 29 To date there is no definitive evidence for a primary role of these genes in parathyroid carcinoma, although altered expression of these gene products may participate in the process of malignant transformation. After the report of Cryns et al.,30 showing loss of Rb protein expression in parathyroid carcinoma, the absence of this protein in parathyroid tumors was proposed as a tool for the diagnosis of parathyroid malignancy. Since then, however, conflicting results have been reported by other investigators in terms of whether Rb gene alterations are specific for parathyroid cancer.31-33 Moreover, Shattuck et al.34 failed to detect microdeletions, insertions, or point mutations in the coding and promoter regions of the Rb gene in parathyroid carcinomas. The HPT-JT syndrome has provided the best evidence for a defined gene in parathyroid cancer. The gene is known now as HRPT2 but other terms have been used, such as CDC73 and Clorf 28.22 Evidence points to a strong association between HRPT2 mutations, the gene responsible for HPT-JT, and parathyroid carcinoma.35-37 Parathyroid carcinoma occurs with higher frequency in HPT-JT than in sporadic PHPT (15% versus <1%). Similar germline mutations occur in a subset of kindreds with familial isolated hyperparathyroidism.22, 35, 37-44 The role of the HRPT2 gene in the pathogenesis of sporadic parathyroid carcinoma was shown by Howell et al.35 and Shattuck et al.36 in 2003. In the former study,35 HRPT2 mutations were detected in 4 of 4 sporadic parathyroid carcinomas and in 0 of 25 sporadic parathyroid adenomas. In the later study,36 HRPT2 mutations were found in 10 of 15 patients with apparently sporadic parathyroid carcinoma. Cetani et al.37, 45 identified HRPT2 mutations in 9 of 11 parathyroid carcinomas but in 0 of 4 sporadic atypical adenomas. Most of the mutations are of the nonsense form and are predicted to result in lack of or reduced protein expression of the encoded parafibromin protein (see below) (Fig. 1). The prevalence of HRPT2 mutations in sporadic parathyroid carcinomas may be as high as 76.6% (Table 1). Thus, the strong association between HRPT2 mutation and parathyroid malignancy suggests that this molecular event is involved in the pathogenesis of most sporadic parathyroid carcinomas. Of particular interest is the demonstration that germline mutations were identified in about one third of subjects.36, 37, 45 This finding suggests that a subset of patients with apparently sporadic parathyroid carcinomas may have the HPT-JT syndrome or a variant. Inactivating mutations of noncoding or regulatory regions could also be implicated in the pathogenesis of sporadic parathyroid carcinoma and might be present in those without alterations in the coding regions of the gene. A recent study by Haven et al.46 found HRPT2 inactivating mutations in only 4 of 28 (15%) cases of parathyroid carcinomas. Two mutations were germinal. These tumors were classified as malignant on the basis of pathological criteria alone without the requirement for malignant behavior. In this study, the exons that harbor 85% of all known mutations (1, 2, and 7) were completely screened. The low mutation frequency could be explained in part by the fact that not all exons could be completely evaluated because of the nature of the formalin-fixed–embedded tissue. Another mechanism of HRPT2 gene inactivation, methylation of the promoter, has been reported in 2 of 11 parathyroid carcinomas.47 HRPT2 mutations in sporadic parathyroid carcinomas. Mutations are designed according to the format generally used in the HRPT2 literature with single-letter amino acid codes. Mutations in bold are germinal.36, 37, 45, 46 *This mutation has been found in three unrelated kindreds.36, 37 HRPT2 mutations are found, but only rarely, in sporadic benign parathyroid adenomas.22, 35, 37, 48 The overall prevalence among the 167 cases of benign disease in which an HRPT2 mutation has been sought is only 1.8%, or even lower 1/120 (0.8%) if the cases from Carpten et al.,22 which were selected for cystic features, are excluded. These observations indicate that HRPT2 mutations have a very limited, if any, role in the pathogenesis of typical sporadic adenomas. HRPT2 encodes a protein of 531 amino acids called parafibromin (parathyroid disease and fibro-osseous lesions) that is evolutionarily conserved22 and similar in homology (54%) to a protein of Saccharomyces cerevisiae known as Cdc73. Cdc73 is a component of yeast RNA polymerase II/Paf1 complex, which is involved in the transcription elongation and RNA processing pathways. A human counterpart to the yeast Paf1 complex has been identified.49-51 Parafibromin is mostly a nuclear protein with a functional bipartite nuclear localization signal (NLS) at residues 125–139 (nucleotides 373–417), which is evolutionary conserved and critical for its nuclear localization.52-54 Specific HRPT2 mutations, identified in HPT-JT or sporadic parathyroid carcinoma and predicted to truncate parafibromin upstream of or within the NLS, disrupt nuclear localization.53 Parafibromin is also localized to the nucleolus. Three nucleolar localization signals at residues 76–92, 192–194, and 393–409 have been identified.55 The role of parafibromin as a tumor suppressor protein comes from the observation that parathyroid tumors carrying HRPT2 mutations are frequently associated with loss of parafibromin expression or function. Transient overexpression of wildtype parafibromin in HEK-293 and NIH3T3 cells, but not its L64P mutant, which is implicated in parathyroid cancer, inhibited cell proliferation by blocking cyclin D1 expression.56 Thus, it is conceivable that, after biallelic HRPT2 inactivation, the inhibitory effect of parafibromin on cyclin D1 activity is lost, leading to neoplastic transformation in susceptible tissue such as parathyroid glands.56 Direct evidence of the anti-proliferative effect of parafibromin was first reported by Zhang et al.57 in several cell lines by showing that some disease-associated HRPT2 mutant constructs abolished the ability of wildtype parafibromin to suppress colony formation. Iwata et al.58 have recently confirmed that the transient overexpression of parafibromin inhibited the growth of HEK293 or NIH3T3 cells. Conversely, in cell lines expressing the large T (LT) antigen, such as 292T and COS-7 cells, transient overexpression of parafibromin increased cell proliferation. Thus, in LT-expressing cells, parafibromin could favor tumorigenesis. The existence of a connection between parafibromin function and components of the transcription machinery is further supported by the fact that the Drosophila ortholog of human parafibromin, hyrax, binds to β-catenin/armadillo and is required for the nuclear transduction of the Wnt/Wingless pathway.59 Finally, Lin et al.53 showed that wildtype, but not NLS-mutant, parafibromin promotes apoptosis in transfected cells. Inhibition of endogenous parafibromin expression by RNA interference decreases the basal and cytotoxic-induced apoptosis. These observations establish the central role of parafibromin in the control of the cell cycle and subsequently in determining cell fate and promoting tumorigenesis. The relationship of parafibromin with the complex network of nuclear components merits further study. Parathyroid carcinomas are typically large (>3 cm), irregular, grayish-white, hard tumors often adherent tenaciously to adjacent tissues.2, 4, 60 The finding of gross infiltration of contiguous structures strongly suggest the diagnosis of carcinoma. The histological criteria of parathyroid carcinoma are difficult to define and identify. Schantz and Castleman61 in 1973 established a set of criteria, including thick fibrous bands, mitotic activity, and vascular and capsular invasion. Generally, neoplastic cells (usually chief cells) are arranged in a lobular pattern and separated by dense trabeculae, with mitotic figures. Invasion of the capsule is rather common and, less frequently (10–15%), vascular invasion also occurs.60 Capsular invasion is characterized by a “tongue-like” protrusion through the collagenous fibers and should be distinguished from pseudoinvasion, because of “trapping” of tumor cells within the capsule, which can be found in adenoma.2, 62 The criteria of vascular invasion have been differently defined according to whether capsular vessels or vessels in the surrounding tissues are involved.2, 62, 63 Partial attachment of tumor cells to the wall of the vascular channel or thrombosis should also be present.2, 63 Because metastatic behavior is rare at presentation,64 the diagnosis of parathyroid cancer on the basis of the above morphologic criteria may be difficult at the time of the initial operation. Many of the features described above, such as adherence to surrounding tissues, fibrous bands, trabecular growth, and mitosis, are not pathognomonic of malignancy because they can also be found in parathyroid adenomas. The diagnostic value of capsular and vascular invasion is still debated. Some authors regard vascular invasion as virtually diagnostic of malignancy.2, 64 Thus, controversy and diagnostic uncertainties still exist.2, 62, 63 The distinction between benign and malignant parathyroid tumors is very hard and rarely made at initial histology. Indeed, in a large series of patients with metastatic parathyroid cancers, as many as 50% were initially classified as benign tumors.65 A full discussion of the of parathyroid cancer is the of this In an to diagnostic other histological have been but has clear diagnostic However, the high of HRPT2 in parathyroid carcinomas has the for the development of new diagnostic parafibromin of potential particularly in cases with equivocal initial histology (see of patients have and but parathyroid disease, and those with malignant clinical features will to further the of these diagnostic as markers for parathyroid carcinoma. The clinical manifestations of parathyroid carcinoma are caused by the effects of and hypercalcemia rather than by the local infiltration or distant 2 The typical clinical is characterized by and of severe with in to of and and in to to of patients with parathyroid carcinoma have a neck is a include and and severe disease, and can also of these features is pathognomonic of malignancy. In the of cases, the diagnosis of parathyroid carcinoma is made only in when hypercalcemia because of local of tumor or distant metastases. In some patients with parathyroid cancer, a from is The clinical of this finding in parathyroid carcinoma Rarely, parathyroid carcinomas are can be as or carcinoma because of disease neck caused by for transcription and may the The of metastases is the only of malignancy that is generally but they usually occur in the course of the disease. initial clinical features it can be a to between hyperparathyroidism caused by parathyroid carcinoma and that caused by its much more common benign Because are associated with complete resection of the tumor at the time of initial it is to establish the diagnosis at the time the that might lead to a parathyroid cancer in a patients with PHPT are and in there is no the ratio in PHPT women by a ratio of the age of a with parathyroid cancer is about 10 yr than the with benign and are within 1 above the in most patients with parathyroid and in most patients with parathyroid carcinoma. are in patients with parathyroid carcinoma and only in those with adenomas. and the of both and manifestations at the time of suggests the possibility of parathyroid carcinoma. In benign PHPT, disease is and and is and of the parathyroid parathyroid carcinomas are usually and may be The tissue is hard and and adherent to adjacent Parathyroid are and but not activity is also higher in patients with parathyroid carcinoma than in those with in are generally to the of the and of human may be in patients with parathyroid cancer but not in those with benign were found to be in a of with parathyroid carcinomas, in contrast to a control of patients with benign In the was the form of that is associated with malignancy in and Moreover, of might be of such as and benign PHPT presents with and a clinical that was common but is now seen in most the clinical distinction between benign and malignant disease may be It is to have a high of particularly when kidney and disease are present than to the for by to cancer in the PHPT, called many clinical features with parathyroid carcinoma. In of the of and that are common in parathyroid parathyroid cancer should be in diagnosis of this Parathyroid cancer should also be in without a of prior neck surgery presents with recurrent is used to the of the diagnosis of parathyroid carcinoma. has involved the use of proliferation of cell cyclin has been shown in parathyroid carcinoma with but among these tumor has the of this approach. expression of an of and expression have been shown in carcinomas. The association between these and high has been to the likelihood of of HRPT2 gene to be a more diagnostic of or mutation at the HRPT2 gene and loss or of parafibromin have been reported in the large of parathyroid carcinomas but very rarely in (Fig. To date, are in equivocal cases, where this have the greatest diagnostic (Table It is to that the diagnostic potential of these on common in parathyroid cancer and in benign disease. Because benign parathyroid disease is much more common than parathyroid cancer, a that has a in benign parathyroid disease if have clinical The value of the may be therefore, if the HRPT2 is to cases that are The of parafibromin and HRPT2 gene the likelihood of a on this it to all parathyroid tumors in which the diagnosis is for of both the HRPT2 gene and its of parafibromin A nuclear is present in most parathyroid cells Parathyroid The of cells show a nuclear Parathyroid carcinoma. cells show no nuclear from with from the of Parathyroid carcinoma typically an course because the tumor has a rather low malignant initial very few patients show of or distant 60 Parathyroid carcinoma and to contiguous structures in the occur in the course of the disease with to and in frequency by metastases Rarely, distant metastases occur in and The of HRPT2 mutations in patients with apparently sporadic parathyroid as germline 37, 45, 46 suggests that a subset of these patients might have HPT-JT syndrome or This observation has for the of recurrent disease in parathyroid cancer. a a recurrence of parathyroid cancer, in to the likelihood that the carcinoma has a new tumor should be because parathyroid tumors can in patients with HPT-JT for and is also Moreover, the of a with sporadic parathyroid carcinoma carrying a germline HRPT2 mutation are susceptible to the development of parathyroid cancer or other manifestations of HPT-JT In one such a parathyroid cancer was by neck in an not of with and neck is by et surgery should be at and all parathyroid and of tissue. A the in may also be the for Because of parathyroid cancer in this has not all the HRPT2 gene will the is generally not In those complete of parathyroid tissue to the is not to the of malignant tissue at an is the only for parathyroid carcinoma and of complete resection of the primary at the time of initial this both and are of present with features of parathyroid carcinoma of all parathyroid because parathyroid carcinoma has been reported to with benign or The most is and should be but an neck is only when there is to the the diagnosis of parathyroid cancer is made after parathyroid surgery on the basis of as often the more the of the tumor are typical of a parathyroid carcinoma, and the vascular or capsular invasion or if hypercalcemia further of the neck can be after localization studies (see The structures surrounding the tumor should be as described features are the is and the diagnosis is only on equivocal is not because the complete resection of the tumor may to be However, such patients should be with of and a parathyroid carcinoma has a recurrence of Most occur yr after the initial but this is and a of as as yr has been reported.1, studies should be in all patients of a with of in the should be used with if at to the with of malignant are and for may be The of recurrent or metastatic parathyroid carcinoma is in the neck should be with including the and other involved distant particularly in the of localized metastatic disease, should also be if a tumor may a of to resection of or other of malignant tissue is rarely may result in of from to tumor may also the hypercalcemia more to generally is have been and and alone or in with and but of has to be this has no role in the of patients with parathyroid carcinoma. the of a of an in a with tumor invasion of has if any, effect in parathyroid have the use of irradiation as The reported a at a of 60 in patients The Cancer also suggests a lower local recurrence if was after of the type of and the disease parathyroid carcinoma has metastatic and are clinical a of the and are often used, but in the of cases, that are and may control but patients frequently to is but the is and may be associated with the has been reported to in cases of metastatic parathyroid showed in recent case cell may also be to a Another is to the parathyroid of the parathyroid cell by to that the for Thus, to is A was used for 2 yr in a with metastatic parathyroid cancer with has been by a more with a and more In benign PHPT, and for to 3 Recently, the results of a study of in 29 patients with inoperable parathyroid carcinoma were The primary of the study was the of patients a in from at the of the changes from in and of The of in this study was from that might be in benign to as required to lower of from 1 to reduced hypercalcemia in about of patients with inoperable parathyroid carcinoma (Fig. In the of 29 from to with the greatest seen in those patients with the of at study It was of interest that the in were not by a similar in a 4 after but the was not was it the reason for the in and to unclear at this and were the most common in more than one of all patients at these these of in some cases. including and were not to be they were of the often disease. are no that the course of the parathyroid cancer this should not be to control hypercalcemia in a with a metastatic that is and to However, the suggest that is in and is in many patients at to other for of this can be used in patients with the common in patients with longstanding parathyroid cancer. an new for of hypercalcemia in patients with inoperable disease. in in parathyroid cancer with were in to the The from to from the in inoperable parathyroid carcinoma. The The of parathyroid carcinoma is with The best on and complete of the tumor at initial The time to recurrence is usually 3 although of to yr have been reported.1, the tumor complete is although is still common with from to The National Cancer reported a of and the Cancer reported of 85% and at and 10 The National and recently reported a of The best to parathyroid carcinoma is to it or at the time of parathyroid surgery and for the tumor to be completely at the time of the initial operation. Because the diagnosis is often not clear at the time of recent to between benign and malignant disease both by and are The disease is indolent but progressive. to local and distant metastases can and therapeutic with and are not the of the disease rather than the disease