Parathyroid carcinoma: A review

CLINICAL REVIEW

David W. Eisele, MD, Section Editor

PARATHYROID CARCINOMA: A REVIEW Randall P. Owen, MD, MS,1 Carl E. Silver, MD,2 Phillip K. Pellitteri, DO,3 Ashok R. Shaha, MD,4 Kenneth O. Devaney, MD, JD, FCAP,5 Jochen A. Werner, MD,6 Alessandra Rinaldo, MD, FRCS, FRCSGlasg, FRCSI,7 Alfio Ferlito, MD, DLO, DPath, FRCS, FRCSEd, FRCSGlasg, FRCSI, FHKCORL, FDSRCS, FRCPath, FASCP, IFCAP7 1

Department of Surgery, Division of Metabolic, Endocrine and Minimally Invasive Surgery, Mount Sinai School of Medicine, New York, New York 2 Departments of Surgery and Otolaryngology–Head and Neck Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 3 Department of Otolaryngology–Head and Neck Surgery, Geisinger Medical Center, Danville, Pennsylvania 4 Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, New York 5 Department of Pathology, Allegiance Health, Jackson, Michigan 6 Department of Otorhinolaryngology–Head and Neck Surgery, Philipp-University Marburg, Marburg, Germany 7 Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy. E-mail: [email protected]

Accepted 31 December 2009 Published online 22 March 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21376

Abstract: Background. Parathyroid carcinoma is a rare entity, comprising fewer than 1% of cases of hyperparathyroidism. The disease generally presents with severe hyperparathyroidism and occasionally with vocal cord paralysis or a firm palpable cervical mass. Methods. The classic histopathologic features of trabecular pattern, mitotic figures, thick fibrous bands, and capsular and vascular invasion are not present in every case but are useful in assessing whether a particular hyperfunctional parathyroid lesion is a carcinoma. Nevertheless, recognition of malignancy at initial operation may be difficult. Management primarily involves complete surgical removal through en bloc resection, which may include adjacent central neck structures. Results. Adjuvant radiation therapy has not been proven to be uniformly effective, but several series show results suggestive of a possible survival advantage. Chemotherapy, genetic, and other biomodifying agents remain experimental. Long-term outcome for this neoplasm remains problematic, and complications from intractable hypercalcemia constitute the foremost cause of death. Reported 5-year survivals have ranged between 70% and 85%. Conclusions. Initial surgical success offers the greatest opportunity for cure. Reoperation for recurrence offers the potential for short- and intermediate-term relief from the sequelae of hypercalcemia, but rarely results in cure. Severely elevated calcium levels should be controlled before initial surgery, and much of the treatment for recurrent or persistent disease, including reoperaC 2010 tive surgery, is directed at control of hypercalcemia. V Wiley Periodicals, Inc. Head Neck 33: 429–436, 2011 Keywords: parathyroid carcinoma; parathyroidism; treatment; prognosis

hypercalcemia;

hyper-

Correspondence to: A. Ferlito This review was written by members of the International Head and Neck Scientific Group (www.IHNSG.com). C 2010 Wiley Periodicals, Inc. V

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Parathyroid carcinoma, a rare entity, comprises a small percentage of patients with hyperparathyroidism and is usually not detected until the time of surgery or thereafter. A meta-analysis by Ruda et al1 of 20,225 cases of primary hyperparathyroidism revealed only 0.74% to be parathyroid carcinoma. Data collected by the National Cancer Database (NCDB) on 286 cases of parathyroid carcinoma from 1985 to 1995 found an equal distribution between male and female patients. Mean age was 54.5 years, with a range from 14 to 88 years. No clustering was seen with respect to race, income group, or geographic region. Tumor size was not recorded in 39% of cases, raising the concern that many tumors were removed piecemeal, and thus with a high likelihood of spillage and reimplantation.2 Complete surgical extirpation is the only known curative modality.3 The disease is sufficiently rare that it is difficult to draw rational conclusions with regard to other issues such as the use of adjuvant radiation therapy. A peculiar observation has been a 15% prevalence of parathyroid carcinoma in patients with hyperparathyroidism–jaw tumor syndrome, a subtype of familial hyperparathyroidism.4 This rare form of the disorder results from an autosomal-dominant pattern of inheritance manifest as primary hyperparathyroidism and fibro-osseous lesions of the mandible and maxilla.5 Mutations in the hyperparathyroid type 2 (HRPT2) gene, a tumor-suppressor gene responsible for encoding parafibromin, located on chromosome 1q25, result in the development of this syndrome.6 PATHOLOGY

Although the pathologic features of malignancies of the thyroid gland have been well established, the same

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cannot be said for parathyroid gland carcinoma. This is chiefly explained by the fact that a substantial degree of overlap exists between pathologic features of nonmetastasizing parathyroid adenomas and parathyroid carcinomas with demonstrated metastases. One frequently referenced article from the 1970s, derived from the experiences of the Massachusetts General Hospital,7 provided a description of the pathologic features of 70 cases of parathyroid carcinoma, 50 of which were slide reviews of cases originating from outside institutions. Many subsequent reports on this subject refer back to this article for its description of the histopathologic features of parathyroid carcinoma. Interestingly, an earlier review of the literature by Pollack et al8 in 1961 observed: ‘‘evaluation of malignancy by histological criteria is difficult therefore parathyroid carcinoma has been taken to mean a parathyroid tumor which metastasizes or is locally invasive, and causes hyperparathyroidism.’’ In accord with the Massachusetts General review by Schantz and Castleman,7 light microscopic features distinguishing carcinoma from adenoma include the presence of a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and vascular invasions. Those authors noted that, although all these criteria were not present in each of their cases, several were usually present, with mitoses in the parenchymal cells being the most valuable criterion (90% fibrous trabeculae, 81% mitotic figures, 67% capsular invasion, 12% vascular invasion). It should be noted parenthetically that mitotic figures in endothelial cells will sometimes be encountered in parathyroid adenomas, which means that their presence alone will not be pathognomonic of carcinoma. Both the presence of cellular atypia and a variation in cell size have likewise not proven to be reliable diagnostic criteria for the recognition of parathyroid carcinoma. Most metastasizing tumors of parathyroid origin have proved to have a (disappointingly) bland pattern on light microscopy, although rarely an anaplastic pattern will be encountered. Eighteen of 70 cases from this large series had metastases. The Massachusetts General authors did not find convincing evidence of transition from an adenoma to a carcinoma in their series, although later authors have suggested not only an association between parathyroid carcinomas and hyperplasia but also, in rare instances, adenoma of the parathyroid gland.9 The NCDB report of 286 cases classified the tumors as follows: well differentiated, 80.4%; moderately differentiated, 9.8%; poorly differentiated, 7.8%; and undifferentiated, 2.0%.2 NCDB also identified 15% of cases with lymph node involvement, although survival appeared similar irrespective of whether lymph nodes were involved. Holmes et al10 noted that variations in nuclear size, nuclear hyperchromatism, bizarre nuclei, and giant cells have been observed in 25% of benign parathyroid adenomas, thus making it difficult to discern malignancy of

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the parathyroid. It also may be difficult to differentiate between cancers of the thyroid, parathyroid, and thymus because they may have similar features. Castleman11 stated that all parathyroid carcinomas have mitotic features, but Stephenson Jr12 reported a case of metastatic parathyroid carcinoma with no mitotic features. Bondeson et al13 reported a series of 56 cases in which they noted that although mitotic figures were more frequent in carcinomas, in half of the cases the frequency of mitoses did not exceed values recorded in benign parathyroid lesions. The conclusion was that mitotic activity constituted a prognostic risk factor but was of limited diagnostic significance. In the series of 27 patients from The University of Texas M. D. Anderson Cancer Center in Houston, Texas (hereafter M. D. Anderson),14,15 the following pathologic features were reported: 44% fibrous bands, 40% mitoses, 37% vascular invasion, 26% capsular invasion, 11% trabeculae, and 11% lymphatic invasion. Nineteen of 27 patients had locally invasive disease. Fifteen of 18 patients operated on at M. D. Anderson had carcinoma of a single inferior gland, and this predilection has been reported in other series as well.10,16 It may be surmised from these widely varying reports that there is no single histopathologic feature that is pathognomonic for parathyroid carcinoma. However, there are many features that may help to diagnose or to exclude the diagnosis. Grossly, the tumor is characteristically hard and grayish in appearance, seemingly devoid of the surrounding fatty tissue more characteristic of adenoma. The tumor mass may not be well circumscribed, and it may be adherent to other central neck soft tissue structures connected by dense fascial bands or demonstrating frank invasion. Comedonecrosis within a parathyroid neoplasm suggests malignancy,17 as does extension of tumor beyond the capsule to involve surrounding tissues. Because the disease is rare, the assessment by different pathologists may be expected to vary appreciably as a result of the varying levels of familiarity with endocrine cancers, particularly parathyroid carcinoma. The surgeon’s assessment with respect to the presence of local invasion of surrounding structures is critical in determining whether the lesion is malignant. At the outset of the disease or the initial surgery, it may not always be possible to tell the difference between carcinoma and adenoma. In some patients only the subsequent occurrence of metastatic disease or local recurrence with invasion may determine that the original lesion was a parathyroid carcinoma. Additional problems in distinguishing parathyroid cancer from benign disease may occur with ‘‘atypical parathyroid adenoma,’’ a subset of tumors that share some of the characteristics of carcinoma (eg, mitoses, fibrosis, capsular invasion), but lack unequivocal evidence of invasive growth.18 Guiter and DeLellis19 investigated a series of these tumors in 24 patients, the characterization of which was based on peritumoral and intratumoral fibrosis, mitoses, cytologic

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atypia, and possible capsular invasion. The most prevalent features were intracapsular tumor (87%), intratumoral fibrosis (75%), cystic degeneration (50%), mitoses (29%), and peritumoral fibrosis (25%). Frank extension of tumor beyond the capsule and vascular invasion were noted in only a single patient each, and none had necrosis. Clinical and pathologic staging has not been established for parathyroid carcinoma for several reasons. First, it has not been shown that the size of the tumor has any impact on prognosis. Second, lymph nodes are seldom involved, and also have a questionable impact on prognosis. Finally, with the rarity of this entity, and the inability of these basic tumor features to predict outcome, it would be misleading to classify these cancers in an arbitrary way. However, in their editorial, Shaha and Shah20 suggested a future staging system for parathyroid cancer. They assigned the T classification depending on the size of the tumor and involvement of the surrounding soft tissues or major organs. The suggested classification system appears to be quite practical and will help in the future to compare the results from various series and to develop rational consensus in the management of parathyroid cancer. As with other challenging areas of pathologic diagnosis, it would be only natural to turn to molecular studies for further insights into the nature of carcinomas of the parathyroid gland, with the hope that some diagnostic aids might thus be elucidated. Cyclin D1 overexpression, for example, is found in the majority of parathyroid carcinomas, although it also appears in nearly half of adenomas.9 It may be that the retinoblastoma 1 (RB1) gene is inactivated more frequently in parathyroid carcinoma than that in adenoma, although it remains to be seen whether this will translate into a useful diagnostic testing strategy.21,22 In conclusion, the surgical pathologist must rely on a variety of factors with regard to the diagnosis of parathyroid carcinoma. Because >97% of cases of hyperparathyroidism result from benign disease, the rarity of parathyroid carcinomas brings them into differential diagnostic consideration only uncommonly. The clinical features of severe hyperparathyroidism, as discussed in the following text, may be taken into consideration. The surgeon will often report that dissection of the mass was surprisingly difficult in the patient with parathyroid carcinoma, with unexpected adherence to the surrounding soft tissues. Finally, the light microscopic findings of mitotic activity, atypical mitoses, vascular space invasion, fibrous bands within the tumor, capsular invasion with extension into the surrounding soft tissue, a trabecular growth pattern, and the presence of macronucleoli may all serve to raise in the pathologist’s mind the possibility of an aggressive lesion in the patient, although none of these features alone will prove a diagnosis of malignancy. Pathologic differential diagnostic considerations in a patient with a suspected parathyroid carcinoma

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include: parathyroid adenoma; malignancy of thyroid and not of parathyroid origin; and metastatic tumors derived from another (occult) site, such as, for example, renal cell carcinoma. One final potential pitfall is the patient with a benign lesion who has previously undergone neck exploration in whom, upon pathologic examination, the consequent postsurgical scarring may simulate an invasive process. CLINICAL FEATURES

Parathyroid cancer generally presents with the signs and symptoms of hyperparathyroidism. Symptoms may include fatigue; bone, joint, and muscular pain; headaches; polyuria; weight loss; dyspepsia; constipation; anorexia; and nausea. Symptoms arising from secondary manifestations of hyperparathyroidism, such as nephrolithiasis and osteoporosis, may also be present. Severe hypercalcemia may result in lethargy, confusion, stupor, and coma, although many patients with hypercalcemia have either mild symptoms or none at all. Physical examination is generally unrevealing in patients with parathyroid cancer, although there are 2 signs that should alert the examiner to the possibility of cancer in a patient with hyperparathyroidism. The first is a paralyzed vocal cord. This is never the result of a parathyroid adenoma, and thus, until proven otherwise, the patient should be considered to have a thyroid or parathyroid carcinoma on the side of the paralysis. The second sign is a palpable cervical mass. In most patients with hyperparathyroidism, a palpable mass on physical examination is attributed to a coexistent thyroid tumor. However, a palpable mass of parathyroid tissue is indicative of carcinoma. Fineneedle aspiration biopsy (FNAB) may be most helpful in this respect. At the present time, neck mass has become uncommon in patients with parathyroid carcinoma. Busaidy et al14 reported that of 27 patients from M. D. Anderson from 1980 to 2002, 4 patients (15%) had a palpable cervical mass. In an earlier series of 14 patients seen at M. D. Anderson from 1968 to 1982, 4 patients (29%) had a palpable mass,23 and among 43 patients seen at the Mayo Clinic from 1920 to 1990, 14 patients (45%) had a palpable mass.24 The study reported by Schantz and Castleman7 indicated a palpable mass in 31% of patients. It is likely that in series that include patients seen before the era of calcium screening and parathyroid hormone (PTH) assays, the disease was detected at a more advanced state, thus giving rise to a higher percentage of patients with a palpable mass. Concurrent elevations in PTH and calcium levels are diagnostic of hyperparathyroidism. These levels are thought to be somewhat higher in patients with parathyroid cancer, although it is possible to have high levels in benign disease, and unremarkably elevated levels in patients with cancer. In the study reported by Schantz and Castleman,7 the average calcium level was 15.2 mg/dL. The M. D. Anderson

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series reported an average calcium level of 13.4 mg/ dL.7,14 It is also possible to identify a parathyroid lesion on ultrasound performed to examine the thyroid gland. In a cohort of 6496 patients, 24 (0.4%) were found to have incidental parathyroid lesions. ‘‘The use of FNA-PTH combined with FNAB can help clinicians accurately diagnose parathyroid lesions at the time of US-guided FNAB.’’25 Gates et al26 showed in their investigation of 24 patients with biochemically confirmed hyperparathyroidism that the general preoperative thyroid ultrasound is able to reveal coexisting parathyroid disease. This statement confirms the value of ultrasound diagnosis within the discussed context. Because most cases of parathyroid cancer are not identified until the time of surgery, or even thereafter, it is impossible to make recommendations for preoperative imaging, unless cancer is suspected. Schoretsanitis et al27 explained that parathyroid scintigraphy and ultrasound are useful for localization of all parathyroid lesions and that CT, MRI, and positron emission tomography (PET) scans may be useful in evaluation of the extent of primary lesions and metastases in parathyroid carcinomas. In a series of 14 reoperative cases, Iacobone et al28 reported the use of at least 2 imaging modalities (ultrasound, CT, MRI, and/ or scintigraphy). Concordance between imaging and operative findings reached 100% with the combination of ultrasound and scintigraphy, but was as low as 64% with scintigraphy and either CT or MRI. Based on experience and these results, it seems appropriate to obtain reliable imaging before reoperating on a patient with parathyroid cancer, to provide the best possible information on localization and extent of the tumor. About 20 cases of nonfunctioning parathyroid carcinomas have been reported in the literature. These tumors do not secrete PTH and thus do not cause hypercalcemia or its sequelae. Therefore, the tumors are generally not identified until they exert a mass effect and are very large. They are treated by surgical excision, although it may be challenging to obtain negative margins with an extensive tumor. As opposed to functional parathyroid cancers, patients with nonfunctional tumors eventually die from mass effect and systemic tumor burden rather than from hypercalcemia.29 The diagnosis of parathyroid carcinoma is always difficult and is usually controversial. The preoperative evaluation of the patient with severe hypercalcemia and high PTH levels should lead to consideration of the possibility of parathyroid carcinoma. In most patients, intraoperative findings are strongly indicative of cancer, particularly if the tumor is adherent to the thyroid gland, central neck soft tissues, or aerodigestive structures. In such instances, it is prudent to proceed with en bloc resection of the involved gland, with inclusion of the ipsilateral thyroid lobe, thymic horn, central compartment lymph nodes, and surrounding superior mediastinal soft tissues. Attempts

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to separate the parathyroid tumor in such instances will risk effraction of the capsule and result in tumor spillage, raising the risk of parathyromatosis and unresectable diffuse local recurrence. Kebebew et al30 have identified the lack of an en bloc resection resulting in parathyromatosis as the most common cause of initial surgical failure in parathyroid carcinoma. A pathologic diagnosis on frozen section may be quite difficult, particularly considering the difference between atypical parathyroid adenoma and parathyroid carcinoma, as described in the previous section. As such, the final diagnosis of parathyroid carcinoma rests on the presence of frank gross invasion of central neck structures, nodal and/or distant metastases, or recurrent disease. Quite often, the pathologist will report that the parathyroid tissue is suspicious for parathyroid carcinoma, and clinical correlation is suggested. MANAGEMENT Surgery. Prior to surgery, severe hypercalcemia should be treated as discussed in the following text. Surgery should not be done on an emergency basis but rather once the patient’s calcium level has been stabilized by nonsurgical means. Surgery remains the primary management modality in the treatment of parathyroid cancer. Parathyroid tissue, whether benign or malignant, is known to easily reimplant, to establish a new blood supply, and to remain functional. Accordingly, it is well accepted that proper surgical technique for eradication of parathyroid carcinoma entails en bloc resection of the tumor and adjacent surrounding central compartment tissues. In the absence of proven malignancy, the surgeon may be reluctant to sacrifice structures such as the recurrent laryngeal nerve or tracheoesophageal complex. Further complicating the diagnostic dilemma is that intraoperative frozen section may be of limited value because of varying pathologic features of these tumors and similarity to benign parathyroid lesions. Thus, if the lesion is removed without certainty of malignancy, there may be a greater likelihood of reimplantation, with resulting development of parathyromatosis and recurrence. If the diagnosis of parathyroid cancer is known or is strongly suspected by reason of clinical, radiographic, or intraoperative findings, an en bloc resection to prevent recurrence is warranted. In the M. D. Anderson series, there was no difference in survival related to the type of surgery done (simple excision vs en bloc), whereas in the San Francisco series reported by Kebebew et al,30 local resection leading to tumor spillage and parathyromatosis was a strong predictor of recurrent disease. Given these findings collectively, it would appear that en bloc resection offers the best opportunity for surgical cure at initial operation. The surgery of parathyroid carcinoma is currently performed generally via an open approach. En bloc

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resection of the tumor with safe margins is the imperative aim of surgical treatment. To what extent endoscopic procedures or even robotic systems, as they are described for papillary thyroid carcinomas,31,32 may be applied for planned surgery of parathyroid carcinomas must be further evaluated. Lymphadenectomy of the paratracheal region (level VI) accompanying en bloc resection is warranted.33 However, elective lymphadenectomy of regional lymph nodes other than level VI is not recommended because lymph node metastases are uncommon and no therapeutic benefit has been established.34 Reoperation with metastasectomy has been shown to decrease PTH and calcium levels and to improve symptoms and is thus recommended when feasible. Mediastinal dissection may be required for extension of soft tissue disease through the thoracic inlet, in combination with central compartment neck dissection. Kebebew et al30 suggest that localization studies should be undertaken for mapping of tumor recurrence and to rule out distant metastasis. A combination of physiologic and anatomic imaging studies should be concordant in identifying tumor sites. This may be accomplished with nuclear scintigraphy (sestamibi) together with high-resolution ultrasound, CT, or MRI. In this series the highest rate of concordance was shown to occur with sestamibi and ultrasound (71%). One of the current authors (P.K.P.) uses image fusion with sestamibi and CT for identification of hyperfunctional parathyroid tissue, including parathyroid cancer. Unfortunately, despite modern imaging and radical procedures, reoperations for parathyroid cancer are rarely if ever curative.28 Intraoperative nerve monitoring is not mentioned in any of the series of parathyroid cancer referenced herein. However, 1 of the current authors (R.P.O.) has used it, with success, in reoperative parathyroid cancer operations. Because there is often significant scar tissue and abnormal anatomy in such cases, it is reasonable to use this new technology to increase the safety and efficacy of identifying the nerve early and with certainty. This may enable the surgeon to perform a more complete exploration and en bloc resection of the recurrent cancer and surrounding tissues, without giving rise to fear of unnecessary nerve injury. Yarbrough et al35 described the use of intraoperative nerve monitoring in 52 cervical reexploration procedures. The authors did not find a difference between the monitored group and the unmonitored group with respect to recurrent nerve injury, but it would appear that the cohort was too small to detect any statistically significant difference, given that only 1 injury occurred in each group. Radiation. The M. D. Anderson group treated 6 of 18 patients with invasive parathyroid cancer with adjuvant radiotherapy (RT) in doses of 50–63 Gy. Five of 6 did not recur locally. Five of 12 who did not receive RT recurred, suggesting the possibility that

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radiation was effective in preventing recurrence. However, this is a very limited retrospective observation, with no attempt to show that these 2 groups of patients had similar characteristics or that the difference in outcomes was statistically significant. The authors noted that, although these data are intriguing, ‘‘the small numbers of patients precluded quantitative analyses.’’14,15 Munson et al36 reviewed a series of 61 patients treated at the Mayo Clinic. Fifty-seven of these patients were treated with surgery alone; 4 patients were treated with surgery and adjuvant radiation therapy; and 25 patients (44%) had locoregional recurrence at a median of 27 months after surgery. All 4 patients who received adjuvant radiation (between 66 and 70 Gy) were alive, with no evidence of disease after an average of 60 months’ follow-up. Univariate analysis examining age, institution where initially treated (Mayo Clinic or ‘‘other’’), tumor size, weight, surgical margins, and vascular invasion was performed. A p value of .06 was identified for venue of treatment, favoring patients treated initially at the Mayo Clinic, and a p value of .03 was identified favoring negative versus positive margins. However, only 24 patients had margin status recorded. The more robust statistical method of multivariate analysis was not reported here, undoubtedly because the small cohort of patients did not afford sufficient statistical power to achieve a significant result. Without multivariate analysis, variable interactions and confounding factors cannot be ruled out. The lack of such analysis should prompt a conservative assessment of certain conclusions, in particular, the following: ‘‘the risk of postoperative disease progression can be predicted by surgical margin status and the institution at which the initial surgery is performed,’’ and ‘‘radiation therapy can be used to provide local-regional control of recurrent disease.’’ The rarity of this disease renders a randomized prospective trial extremely difficult, thus hindering the possibility of generating sufficient statistical power through a large number of patients to produce reliable results. Therefore, we must glean what is available from studies such as the Mayo Clinic series and make clinical decisions based on limited science.

Chemotherapy and Biotherapy. No curative chemotherapy has been identified for parathyroid carcinoma. However, there are several case reports of biochemical responses and tumor shrinkage and/or necrosis associated with clinical responses up to 5 months in duration. Agents used include dacarbazine (DTIC)37; a combination of DTIC, cyclophosphamide, and fluorouracil38; and a regimen of combined methotrexate, adriamycin, cyclophosphamide, and 1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea (CCNU), which produced a complete response in a nonfunctioning parathyroid carcinoma after 18 months of treatment.39

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Over the last decade, several exciting new biologic agents have been investigated for their potential activity against parathyroid cancer.40 The gene product parafibromin appears to inhibit cell proliferation, blocking expression of cyclin D1, key in parathyroid neoplasia. It is underproduced in cells with a mutation of HRPT2, which is considered a tumor-suppressor gene. A high percentage of patients with parathyroid cancer have an HRPT2 mutation.41,42 Cyclin D1 (also known as parathyroid adenoma 1 [PRAD 1]) is an oncoprotein overexpressed in 18% to 40% of adenomas and in 91% of carcinomas.43,44 These genetic findings may present an opportunity for targeted therapies in the future. Telomerase activity has been reported to be present in parathyroid cancer cells but not in parathyroid adenoma cells. Azidothimadine (AZT) applied in vitro to parathyroid cancer cell lines from 2 different cancer patients blocked telomerase activity, thus inhibiting proliferation and inducing apoptosis. AZT has also been investigated with some success versus other telomerase-active cancers.45,47 A clinical trial would be helpful in establishing the efficacy of AZT in parathyroid cancer. Preliminary experiments in single human cases have shown some limited efficacy of immunotherapy. In a single patient, PTH peptides were injected, eliciting a humoral response, and, in a second patient, dendritic cells exposed to PTH and tumor lysate were injected into inguinal lymph nodes.47 None of these studies resulted in an effective treatment regimen for patients with parathyroid cancer, but obviously continued study is necessary to develop nonsurgical treatments for patients for whom surgery is not an option or where surgery has failed. Treatment of Hypercalcemia. Parathyroid cancer typically threatens the patient’s life by uncontrollable levels of hypercalcemia. Mass effect from the tumor rarely produces symptoms or life-threatening vital organ involvement. The treatment of hypercalcemia is particularly relevant in the patient with recurrent or metastatic parathyroid cancer. Because patients with unresectable disease generally die of hypercalcemia, extensive measures may be taken to reduce calcium levels. Furthermore, patients requiring reoperative surgery for palliation may benefit preoperatively from some of these measures, to increase the safety of the operation. Severe hypercalcemia, on initial presentation, should be treated with intravenous (IV) administration of fluids, diuretics, pamidronate, and calcimimetic agents, such as cinacalcet, prior to any surgical treatment. Rehydration with IV saline is foundational. Loop diuretics are given to increase renal calcium excretion. Bisphosphonates are effective but lose efficacy over time. Corticosteroids and calcitonin can be administered but are short-lived in their effect.9 Amifostine decreases PTH secretion but has significant side effects.48 Octreotide has produced modest

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reduction in PTH secretion.49 Radiofrequency ablation and embolization of liver metastases also had a beneficial effect in 1 patient (4 months’ relief from hypercalcemia).50 Cinacalcet was investigated in a single-arm dosetitration trial with 29 participants diagnosed with parathyroid carcinoma, who received up to 360 mg/dL of drug. Calcium reduction of at least 0.25 mmol/L (1 mg/dL) was seen in 62% of participants, with a decline in mean serum calcium of 0.42 mmol/L. The greatest reduction was seen in patients with the highest calcium levels. Five withdrew as a result of adverse effects, and 7 patients died while on study or within 30 days of withdrawal.51 Given that most patients who succumb to parathyroid cancer die of hypercalcemia, cinacalcet may represent a significant adjunct in treatment. Follow-up. Follow-up of patients diagnosed with parathyroid cancer is critical. This includes examination at intervals of 4 to 6 months, with appropriate biochemical studies, including serum calcium levels and PTH levels. A serial rise in PTH levels is suggestive of recurrent parathyroid cancer. Under such circumstances, appropriate imaging studies should be performed to locate the recurrent tumor, which invariably is in the area of the primary tumor or lymph node metastasis. The evaluation should normally include physiologic imaging with sestamibi together with ultrasound of the neck. Cross-sectional imaging such as CT or MRI may be very helpful for correlation of physiologic uptake of sestamibi in the mediastinum. The value of PET imaging in follow-up remains undefined at this time. If the patient does have recurrent disease, the most important decision to be made is whether the tumor is surgically resectable. PROGNOSIS

The only series reporting survival in parathyroid carcinoma patients are those in which surgery was the primary treatment modality. The M. D. Anderson series of 27 patients showed a 5-year survival of 85% and a 10-year survival of 77%.14 The 5 patients in the series who succumbed to parathyroid cancer died of hypercalcemia. The authors reported no significant association between any demographic or pathologic feature and prognosis. The Mayo Clinic series of 43 patients reported a 5-year survival of 69%.36 The NCDB reported a relative survival (this value is different, ie, generally higher, than overall survival) of 86% at 5 years and 49% at 10 years.2 Their report did not show that tumor size or lymph node involvement had any impact on prognosis. Schantz and Castleman7 reported no association between number of mitoses or vascular invasion and prognosis. CONCLUSIONS

Parathyroid carcinoma is a rare entity that generally presents with hyperparathyroidism and, occasionally,

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with vocal cord paralysis or a firm palpable cervical mass. The classic pathologic features of a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and vascular invasions are not present in every case but are useful in assessing whether a particular lesion is a carcinoma. Recognition of malignancy at initial operation may be difficult. The primary means of treatment is surgery, which is the only curative modality. En bloc excision is recommended when the diagnosis of parathyroid cancer is known preoperatively or intraoperatively. Adjuvant radiation may improve cure rates. Cytotoxic, genetic, and other biologic agents have shown some promise, but are experimental. Most deaths in parathyroid carcinoma are attributed to hypercalcemia. Severe hypercalcemia should be controlled before initial surgery, and much of treatment for recurrent or persistent disease, including reoperative surgery, is directed at control of blood calcium levels. Reported 5-year survivals have ranged between 70% and 85%. In addition to the above-cited case series, there are different studies in the literature summarizing patient populations,52,53 whereas the significance of the analyzed results is limited because of the quality of partly very heterogeneous and retrospective data.

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