Parathyroid carcinoma

Surgical Oncology xxx (2014) 1e8

Contents lists available at ScienceDirect

Surgical Oncology journal homepage: www.elsevier.com/locate/suronc

Review

Parathyroid carcinoma Abbas Al-Kurd a, Michal Mekel b, Haggi Mazeh a, * a b

Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel Department of Surgery, Rambam Health Care Campus, Haifa, Israel

a r t i c l e i n f o

a b s t r a c t

Article history: Accepted 25 March 2014

Parathyroid carcinoma is a rare form of endocrine malignancy accounting for only a small minority of cancer cases. Due to the rarity of this cancer, there are no generalized guidelines for its management; however, surgery remains to be the mainstay therapy. The purpose of this article is to review and summarize the available literature on parathyroid carcinoma, while discussing proposed staging systems and the role of available adjuvant therapies. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Parathyroid Carcinoma Review Management

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology and pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis e general considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recurrent disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical management of severe hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

* Corresponding author. Department of Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem 91240, Israel. Tel.: þ972 2 5844550; fax: þ972 2 5844584. E-mail addresses: [email protected] (A. Al-Kurd), [email protected] (H. Mazeh).

Parathyroid carcinoma is a rare endocrine malignancy, accounting for an estimated 0.005% of all cancers [1e6]. This entity was first described by the Swiss surgeon Fritz De Quervain in 1904 [7], and since, less than 1000 cases have been reported in the literature worldwide [1,5,8]. It is generally accepted that parathyroid carcinoma accounts for less than 1% of cases of primary

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A. Al-Kurd et al. / Surgical Oncology xxx (2014) 1e8

hyperparathyroidism [5,9], however, this number has been reported to be higher in some publications, reaching up to 5% [10e 13]. Due to its rarity and the paucity of large-scale published series of patients with parathyroid cancer, there still is a lack of understanding of the natural course and prognostic implications of this disease. In addition, there is still no clear consensus regarding its management and follow-up. The purpose of this review is to discuss and summarize the available literature on parathyroid carcinoma, and to explore the currently recommended modes of treatment of this rare malignancy. Epidemiology Unlike parathyroid adenoma, which is three times more common in females than in males, no gender preponderance has been demonstrated in parathyroid carcinoma [5,6,14,15]. The mean age of presentation is reported to be between 45 and 59 years, which is a decade younger than that in patients with parathyroid adenomas [5,6,15]. No disproportionate clustering by race, income level, or geographic region has been demonstrated in the literature. The SEER (Surveillance, Epidemiology, and End Results) cancer registry identified 224 patients with parathyroid carcinoma from 1988 to 2003. During this time period, the incidence of parathyroid cancer was found to be very low (<1 per million population per year), however, incidence was shown to increase from 3.58 to 5.73 per 10 million population when comparing the first three years to the last three years of the study. It was assumed that this increase may be secondary to routine serum calcium screening, which may have identified more patients with asymptomatic parathyroid carcinoma [4]. Etiology and pathogenesis The etiology of parathyroid cancer is unknown, and to date, no established predisposing factors have been identified. However, history of neck radiation is a known risk factor of head and neck cancers, and cases of patients with parathyroid carcinoma who previously received radiation therapy to the neck have been described [11,16e19]. Other associated factors previously described include secondary and tertiary hyperparathyroidism caused by chronic renal failure [20]. Currently, there is no evidence that parathyroid carcinoma arises from malignant transformation of preexisting parathyroid or thyroid lesions. However, an association between parathyroid cancer and hyper-functioning parathyroid glands or thyroid cancer has previously been observed [15,21,22]. Parathyroid carcinoma may occur sporadically or as part of a genetic syndrome. These syndromes include MEN1, MEN2A, and isolated familial hyperparathyroidism [3,23e26]. In addition, 15% of patients with hyperparathyroidism jaw tumor syndrome (HPT-JT), an autosomal dominant type of familial hyperparathyroidism, develop parathyroid carcinoma [5,24,25,27,28]. Advances in molecular biology increased our understanding of the pathogenesis of this malignancy. A mutation in HRPT2 (also known as CDC73), a tumor suppressor gene, has been recognized to play a fundamental role in the molecular pathogenesis of parathyroid carcinoma [24]. This gene, which is located on chromosome 1, encodes the protein parafibromin, whose function involves regulation of gene expression and inhibition of cell proliferation. Inactivating germline mutations of this gene are responsible for the development of HPT-JT [27,29]. In addition to the increased risk of parathyroid malignancy, these patients are predisposed to develop ossifying fibromas of the jaw, cystic and neoplastic renal lesions, and uterine tumors [30]. It should be noted that sporadic cases of parathyroid carcinoma have also frequently been shown to be associated with HRPT2

mutations, with a reported rate of 25% [31e33]. In a study attempting to evaluate the value of parafibromin immunostaining in parathyroid carcinoma diagnosis, tumor specimens were obtained from 16 patients with parathyroid adenomas and 8 with parathyroid carcinoma [34]. All were immune-stained with a parafibromin antibody and the expression of parafibromin was analyzed. Parafibromin stained strongly positive in 17 of 18 adenomas (94.4%) (indicating normal expression of parafibromin) and in only 2 of the 8 carcinomas (25%). Negative staining was noted in 3 of 8 carcinomas, and weak positivity was found in 3 of 8 carcinomas. It was concluded by the authors that the loss of parafibromin expression (negative or weak positivity) demonstrated 94.4% specificity in the diagnosis of parathyroid carcinomas. However, clinical application of this finding is yet to be established. Other somatic gene mutations have been implicated in the development of parathyroid carcinoma, including abnormal expression of the retinoblastoma and p53 proteins. Also, the presence of an additional tumor suppressor gene on chromosome 13 in the vicinity of retinoblastoma gene has been proposed [35-37]. However, no clinically significant conclusions have been reached, and further investigation is still required.

Clinical presentation Patients with parathyroid adenomas typically present with mild symptoms of hypercalcemia, or are discovered incidentally upon routine blood tests that demonstrate elevated serum calcium levels. In contrast, in patients with parathyroid cancer, signs and symptoms of severe hypercalcemia often dominate the clinical presentation. These include polydipsia or polyuria, myalgia or arthralgia, nephrolithiasis, weakness, fatigue, nervousness, depression, renal insufficiency, pancreatitis, peptic ulcer disease, or weight loss [11,13,38e40]. Skeletal involvement is also common at the time of presentation, and may manifest as bone pain, osteopenia, osteofibrosis, or pathological fractures [15,41]. Renal and skeletal involvement in particular are a prominent manifestations of parathyroid carcinoma, and are reported to occur in some series in up to 80 and 90% of patients, respectively [38,42]. Two to seven percent of patients are asymptomatic [11,38,42,43]. Some patients with parathyroid carcinoma may present with hypercalcemic crisis, also referred to as parathyroxicosis [44]. This life-threatening condition is characterized by azotemia, oliguria and anuria, as well as neurological manifestations such as profound weakness, somnolence and coma. This emergency is usually associated with severe hypercalcemia (>16 mg/dl), and requires urgent medical attention. Parathyroid crisis is reported to be the presenting manifestation in 7e12% of patients with parathyroid carcinoma [11,14,19,45]. However, it should be noted that patients with primary hyperparathyroidism due to benign causes may also present with hypercalcemic crisis. As many as 10% of the patients with parathyroid carcinoma have a nonfunctioning tumor [46,47]. Unlike functioning tumors, patients usually present late, with symptoms related to “mass effect”, including a palpable neck mass, hoarseness (due to recurrent laryngeal nerve involvement), dysphagia or dyspnea [46,48e50]. Rare cases of incidental nonfunctional parathyroid carcinoma have also been described [51]. On physical examination, unlike benign parathyroid tumors which are almost never palpable, a neck mass can be palpable in 40e70% of cases of parathyroid carcinoma [2,8,11,14,38,52]. This finding, in the presence of hyperparathyroidism, should immediately trigger the clinician’s suspicion of a malignant parathyroid tumor. The presence of a paralyzed recurrent laryngeal nerve (as demonstrated by a paralyzed vocal cord on laryngoscopic

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examination) is a rare physical finding, and indicates advanced and invasive disease [38]. Fifteen to thirty percent of patients are found to have regional lymph node involvement at presentation and approximately one third have distant metastatic lesions [3,5,6,21,40]. The most common site of metastasis in parathyroid carcinoma is the lung [53], followed by liver and bone [40,54]. In many patients, diagnosis is only made by intraoperative findings and is confirmed by a postoperative pathological report consistent with parathyroid carcinoma. This is due to the fact that often the preoperative clinical and biochemical characteristics of patients are indistinguishable from benign causes of hyperparathyroidism [15]. Intraoperative findings suggestive of malignant disease are mentioned later in this review. Laboratory findings Patients with parathyroid carcinoma typically present with a serum calcium level that is greater than 3.5 mmol/L (14 mg/dl), a finding present in 65e75% of cases [11,38,42,43]. In addition, a parathyroid hormone (PTH) level 3e15 times the normal upper limit is extremely suggestive of the disease [1,3,21,40]. In Talat et al.’s review of 330 patients, the mean PTH value at time of diagnosis was found to be 4.5-fold above the upper limit, with a range between 1.0- to 76.1-fold [55]. A recently published study showed that a PTH level 10 times or more than the upper normal limit had a positive predictive value of 81% for parathyroid carcinoma [56]. Also, levels of alkaline phosphatase and a- and bsubunits of human chorionic gonadotropin may be higher in patients with carcinoma compared to those with an adenoma [13,15,57,58]. As expected, both calcium and PTH levels are within normal range in patients with nonfunctioning parathyroid cancers. Imaging Prior to surgical treatment, most patients undergo imaging studies to confirm the diagnosis and localize the diseased gland. The sensitivity and specificity of these diagnostic techniques are increased when they are used in combination. Nevertheless, in current common practice, at least one imaging modality is sufficient to proceed with surgery [2,59,60]. The commonly used imaging studies include ultrasonography, Technetium-99m sestamibi scanning with single-photon emission computed tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Ultrasonography is probably the most widely used of these studies due to its noninvasive and inexpensive nature [14]. Reeder et al. demonstrated that ultrasound imaging has 100% accuracy in detecting parathyroid lesions of 1 cm and above [61]. Although this modality cannot definitely detect malignancy, certain sonographic features may be suggestive and may add to an overall clinical picture indicating the presence of carcinoma [62]. Typical features of carcinoma include a lobulated, hypoechoic appearance, and the presence of a large parathyroid gland, with ill-defined borders [13,63]. Local infiltration, calcification, suspicious vascularity and the presence of a thick capsule have also been found to be factors predictive of malignancy [64]. In addition, ultrasound imaging may show cervical lymph node enlargement and may suggest invasion of the tumor to surrounding structures. An imaging modality combination commonly utilized is Technetium-99m sestamibi scan along with cervical ultrasound [59]. Technetium Tc99 sestamibi is a lipophilic isotope that is taken up by abnormal parathyroid tissue. It enters primarily into the mitochondria, and preferably attaches to parathyroid tissue due to the

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inherent high metabolic activity seen within this tissue [14]. However, sestamibi scan is a localization study, and provides little benefit in differentiating benign from malignant parathyroid lesions [65,66]. Nevertheless, sestamibi scan has been described as useful in diagnosing and localizing metastatic parathyroid carcinoma [66]. Other studies, such as CT and MRI may be useful when other imaging modalities fail to localize the diseased gland. Once performed, these modalities may provide an accurate anatomical description of the lesion including the extent of local invasion into surrounding structures and also map-out other involved regions. It is generally accepted that utilization of CT and MRI is essential in the identification of metastases and recurrent disease once the diagnosis has been made [2,60]. Kebebew et al. demonstrated that the sensitivity for localizing parathyroid carcinoma in the neck using sestamibi scan, MRI, CT, ultrasound, and selective venous sampling of parathyroid hormone (PTH) was 79%, 93%, 69%, and 83%, respectively [2]. Diagnosis e general considerations The preoperative diagnosis of parathyroid carcinoma can be extremely challenging. Many patients undergo surgery for a presumed parathyroid adenoma with suspicion for a parathyroid cancer being raised only during surgery. In others, the diagnosis becomes evident only after pathological examination of the excised gland. In one study, in 14 out of 27 parathyroid carcinoma patients (52%), the diagnosis was made postoperatively based on histopathologic examination [40]. However, as previously mentioned, certain clinical, laboratory, and radiological findings should significantly raise clinical suspicion of malignant disease. These include symptoms of severe hypercalcemia on presentation, including profound renal and skeletal disease [38,42], or parathyrotoxicosis. The presence of a palpable neck mass in a patient with hyperparathyroidism should greatly raise suspicion of parathyroid carcinoma, as should the concurrent appearance of recurrent laryngeal nerve paralysis and hyperparathyroidism. Calcium levels greater than 3.5 mmol/L (14 mg/dl) [11,38,42,43] and an extremely elevated PTH (3e15 times the normal upper limit) [1,3,21,40] are also greatly suggestive. Finally, certain radiological findings as mentioned above may be suggestive of the presence of a malignant parathyroid tumor. When parathyroid carcinoma is suspected, the performance of a fine needle aspiration (FNA) biopsy should be avoided for two reasons: first, the cytology obtained from FNA biopsies is insufficient to differentiate benign from malignant parathyroid lesions [13,14,68], and second, danger of possible tumor seeding in the biopsy tract has been reported [69]. However, FNA may occasionally be utilized in the setting of suspected metastatic disease or in cases of recurrence, with the purpose to confirm the diagnosis prior to more radical surgical interventions [5,13,21,68,70]. When a postoperative pathological confirmation of parathyroid carcinoma is obtained, a thorough workup to rule-out metastatic disease involving the chest, abdomen, and skeletal system should be carried out. These investigations may include, whole body CT, MRI, and possibly FDG-PET/CT. A bone scan should be performed to rule out bone metastasis [67]. Pathology A typical normal parathyroid gland is an ovoid-shaped yellowish-brown structure measuring on average 2  3  7 mm. The combined weight of all four normal parathyroid glands sums up to approximately 150 mg [71]. Benign parathyroid adenomas are typically soft and flattened, round or oval in shape, with a red-

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Table 1 Parathyroid carcinoma staging system proposed by Shaha et al. Shaha et al. staging system T

T1 T2 T3

T4

N

N0 N1 M0 M1 I II III

M Stage

a b c

IV

Primary tumor <3 cm Primary tumor >3 cm Primary tumor of any size with invasion of the surrounding soft tissues (i.e. thyroid gland, strap muscles, etc) Massive central compartment disease, invading the trachea or the esophagus, or recurrent parathyroid carcinoma No regional lymph node metastasis Regional lymph node metastasis No evidence of distant metastasis Evidence of distant metastasis T1N0M0 T2N0M0 T3N0M0 T4N0M0 Any T, N1, M0 Any T, Any N, M1

brown color [14,72]. Carcinomas on the other hand are firm and grayish-white in color and spherical in shape. Tumors may be surrounded by a thick capsule and may macroscopically invade adjacent structures. They range in weight between 600 mg and 110 g, with the majority weighing between 2 and 10 g [14,38]. On histopathology, parathyroid carcinomas may show uniform sheets of cells arranged in a lobular pattern, separated by dense fibrous trabeculae, mitotic figures in the tumor cells, and capsular and blood vessel invasion [73,74]. A thick fibrous capsule may also be present [72]. Among the several various histopathological descriptions of parathyroid carcinoma reported in the literature, the ones described by Schantz and Castleman are the most widely utilized in distinguishing carcinoma from benign tumors [74]. These characteristics are capsular or vascular invasion, the presence of fibrous bands, and the presence of trabecular patterns and mitotic figures. However, it remains of great importance to consider the overall clinical picture rather than any single histopathological criterion [13,14,75,76]. In certain cases, the diagnosis of parathyroid carcinoma can be made with minimal difficulty. For example, in the presence of vascular invasion, adjacent soft tissue invasion or lymph node metastasis, there is very little doubt that the diagnosis is carcinoma. On the other hand, in some cases, the histopathological diagnosis can be much more challenging [53].

Table 2 Parathyroid carcinoma staging system proposed by Talat et al. (Schulte). Talat et al. staging system T

T1 T2 T3 T4

N

M

Stage

Nx N0 N1 Mx M0 M1 I II III IV

Evidence of capsular invasion Invasion of surrounding soft tissues, excluding the vital organs (trachea, larynx and esophagus) Vascular invasion Invasion of vital organs (hypopharynx, trachea, esophagus, larynx, recurrent laryngeal nerve, carotid artery) Lymph node status not assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastasis not assessed No evidence of distant metastasis Evidence of distant metastasis T1N0M0 or T2N0M0 T3N0M0 T4N0M0 or Any T, N1, M0 Any T, Any N, M1

Staging To date, the American Joint Committee on Cancer has not yet developed a TNM staging for parathyroid carcinoma, primarily due to the rarity of this entity, and there is no universally agreed-upon staging system. Both Shaha et al. and Talat et al. [55,77] have proposed possible staging systems (Table 1, Table 2) [55], however their use is still not widely accepted. In Shaha et al.’s staging system [77], T1 and T2 carcinomas are defined by the size of the lesion (less than and greater than 3 cm, respectively). T3 indicates a tumor of any size with the presence of invasion of the surrounding soft tissues (including the thyroid gland, strap muscles, etc). T4 indicates massive central compartment disease, with invasion of the trachea and esophagus. Furthermore, recurrence of parathyroid carcinoma is classified as T4. The N staging is classified according to the absence or presence of regional lymph node metastasis (N0 or N1, respectively). Similarly, M0 indicates the absence of distant metastasis, whereas M1 indicates its presence. The staging system proposed by Shaha et al. is summarized in Table 1. A further classification system proposed by Talat et al. focuses more on the extent and type of invasion of the tumor rather than the tumor size [55]. It is referred to as the Schulte Staging System, and is summarized in Table 2. Talat et al. [55] also divided parathyroid carcinomas into low risk and high risk. Low risk cancers are described by capsular invasion, or invasion of surrounding soft tissues. On the other hand, a high risk cancer implies the presence of vascular invasion, invasion of vital organs, lymph node metastasis, and/or distant metastasis. In one of Schulte’s recent publications [78], Talat et al.’s classification systems previously proposed were applied to 82 patients. In this analysis, a “differentiated” classification system that further classified high-risk cancer was established. In this classification, low risk cancer corresponded to class I, while high risk cancer was subdivided into vascular invasion alone (class II), lymph node metastasis or organ invasion (class III), and distant metastasis (class IV). A statistically significant overall survival difference was shown between the different classes (98.6%, 79.2%, 71.4%, 40.0%, respectively e p < 0.05), therefore confirming the validity of the classification system in parathyroid cancer.

Management The mainstay modality for the management of parathyroid carcinoma is complete surgical resection [2,5,6,14,19,40,79]. In patients in whom the preoperative clinical findings support the diagnosis of carcinoma, the planned surgical technique should be that of complete ‘en-block’ resection. This should also be the case if intraoperative findings support the presence of parathyroid malignancy (a large and firm parathyroid tumor, with a whitish capsule that is adherent to adjacent structures [44]. En block resection entails excision of the parathyroid tumor along with any adjacent structure that is involved. Nevertheless, it has not been shown that prophylactic thyroid lobectomy provides an improvement in survival in cases where the ipsilateral thyroid lobe is clearly not involved [5,21,40]. In one series [19], the most common sites of invasion were the ipsilateral thyroid gland (89%), strap muscles (71%), ipsilateral recurrent laryngeal nerve (26%), esophagus (18%) and trachea (17%), and it is generally recommended that if tumor invasion is identified in the operation, the involved structure is to be removed as well [21]. It is of great importance that clear gross margins are achieved, and that rupture of the capsule is avoided, in order to prevent tumor spillage and decrease the likelihood of recurrence [8,70,80].

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As previously mentioned, at presentation, 15e30% of patients have cervical lymph node involvement. If preoperative or intraoperative findings indicate lymph node involvement, a therapeutic ipsilateral cervical compartment lymph node dissection is indicated. However, a prophylactic neck dissection in patients without evident lymph node disease is not indicated, as it has not been shown to improve survival but rather increases morbidity [3,81]. The intraoperative use of radio-guided techniques, namely hand-held radio-guided gamma probe, has been extensively described in the surgical management of parathyroid adenomas and hyperplasia, and has been determined useful in the localization of enlarged hyperfunctioning parathyroid glands [82e84] This technique has been shown to be applicable even in patients with negative (non-localizing) preoperative sestamibi scans [85]. Although its specific utilization and benefits in the surgical management of parathyroid carcinoma have not been extensively explored, the usefulness of radio-guided gamma probe in the excision of recurrent parathyroid cancer has been described [86]. It is the authors’ opinion that this modality can be especially beneficial in the precise localization of recurrent parathyroid carcinomas. The use of intraoperative PTH (iOPTH) monitoring has been shown to be useful, and in a patient with suspected parathyroid carcinoma, the post-excisional decrease in PTH to a normal range can reassure the clinician, and indicate complete excision [13,87,88]. Cases of parathyroid carcinoma occurring in the setting of parathyroid hyperplasia have been reported, therefore not performing iOPTH in these patients will lead to lack of surgical cure [89,90]. A possible and common clinical situation is the postoperative pathological diagnosis of parathyroid carcinoma in a patient not suspected to have malignant parathyroid pathology pre-operatively. Upon postoperative diagnosis of malignancy, a second neck exploration is not universally indicated. In the past, when the standard surgical management of parathyroid carcinoma was performing ipsilateral thyroid lobectomy, indications for re-exploration included the presence of gross characteristics typical of a parathyroid cancer, the appearance of a histologically aggressive tumor with extensive vascular or capsular invasion, or persistent hypercalcemia after the initial excision [7,15,52,91]. However, in light of controversy on the need for upfront ipsilateral thyroid lobectomy in current practice, recommendations for re-exploration are not obvious. It is reasonable to deduct that surgeons advocating aggressive en-bloc resection should favor repeat exploration and completion of the thyroid lobe resection. In contrast, repeat thyroid lobectomy will not be performed by those who manage parathyroid cancer not invading the thyroid lobe by parathyroidectomy alone. There is a need for further multi-centric studies in order to clarify this point of dispute. A decrease in hypercalcemia is expected to occur within 24 h post-operatively in patients without distant metastasis, however it may take up to 2e3 days for calcium levels to completely normalize [5,15]. Postoperatively, strict monitoring of serum calcium levels is essential, due to the possibility of development of “hungry bone syndrome”, in which severe hypocalcemia and hypophosphatemia can be symptomatic or even fatal. Therefore patients with symptomatic hypocalcemia should be treated aggressively with oral and/ or intravenous calcium supplementation or even calcimimetic agents. As the bone gradually restores its calcium content, the requirement for these supplements is expected to decrease [5,13,15,92]. If the postoperative calcium level does not decrease, incomplete resection should be suspected, and further diagnostic and therapeutic workup is warranted.

5

Recurrent disease Parathyroid carcinoma has been associated with a high recurrence rate, ranging between 49 and 60% in most series, and up to 82% in some reports [2,3,5,13,15,38,40,43,93]. Most recurrences occur 2e5 years after the initial surgery [8], and the most common site of recurrence is locoregional, probably due to incomplete resection or intraoperative tumor spillage. Follow up is performed using calcium and PTH measurements at regular intervals following surgery, however there are no generalized guidelines regarding the recommended length of these intervals. Nevertheless, it should be assumed that the postoperative follow-up for patients with parathyroid carcinomas should be more frequent than for those with adenomas. Recurrence is generally indicated by elevated calcium and PTH levels [14,76]. After laboratory findings indicate recurrence, a thorough imaging work-up should be performed with the intention of localizing the site of recurrence. These imaging modalities include ultrasound, whole body sestamibi scan, whole body CT, MRI or PET scan and bone scan. In case of inconclusive results from the abovementioned studies, more invasive techniques may be utilized including arteriography or selective venous sampling with measurement of PTH [2,5,7,60]. Furthermore, unlike in the primary diagnosis where FNA is avoided, the use of FNA to diagnose recurrence of parathyroid carcinoma is utilized, and can help differentiate between recurrent malignancy and scar tissue [21]. Once recurrent disease has been localized, the best possible treatment is repeated surgical resection, due to lack of other effective treatments. Re-explorations may be very difficult due to dense scar tissue and lack of clear anatomical planes [5]. Metastatic disease Approximately one third of patients have metastatic lesions at presentation [3,5,6,21,40], however the overall incidence of distant metastasis is difficult to assess due to the rarity of parathyroid carcinoma [94]. The most common site of metastasis is the lung [53], followed by liver and bone [40,54]. Cases of brain metastasis have been described as well [95e97]. When technically possible, the resection of these metastatic lesions is recommended [6,13,21,40]. This may entail performance of pulmonary resections, hepatectomies, bone resections or craniotomies. Although absolute curative treatment is unlikely, these metastatectomies are generally justified for the reduction of severe hypercalcemia that is associated with metastatic disease. In addition to this transient palliative effect, resection of distant metastases has been shown to improve patient survival. This is due to the fact that mortality in advanced metastatic parathyroid carcinoma is linked mainly to severe hypercalcemia, and not to mass effect of the tumor itself [14]. The goal of these resections is to remove all remnant disease with clear margins [13]. Even incomplete resections can lead to periods of normocalcemia that can last months or even years, or may facilitate easier medical control of hypercalcemia [7]. Medical management of severe hypercalcemia In patients who present with hypercalcemic crises (parathyrotoxicosis), surgical management is contraindicated prior to adequate medical stabilization [5]. In addition, patients with extensive metastatic disease not amenable to surgical treatment require medical management of their hypercalcemia, which is the most common cause of death in these patients, rather than tumor burden itself [38,52]. The essentials of management of acute hypercalcemia include intravascular fluid resuscitation with isotonic saline, followed by

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loop diuretic-induced excretion of calcium from the body. Oral calcium intake must be minimized, as should drugs that decrease excretion of calcium, such as thiazide diuretics [5]. Agents that decrease bone resorption (and thereby decrease serum calcium levels) are also utilized, and include bisphosphonates, calcimimetic agents, and calcitonin [98]. Bisphosphonates inhibit osteoclastmediated bone resorption, and have been found to be useful agents for decreasing serum calcium in parathyroid carcinoma [99,100]. Calcimimetics drugs (namely cinacalcet) function by binding to calcium-sensing receptors on the surface of parathyroid cells, thereby increasing the receptor’s sensitivity to extracellular calcium and resulting in a decrease in PTH secretion and serum levels of calcium [13,101e103]. Calcitonin inhibits both osteoclastmediated bone resorption and increases urinary calcium excretion [13], and may have a synergistic effect when used with steroids [104]. However there have been reports of anaphylaxis to calcitonin in patients allergic to salmon [5,105]. Other less commonly used agents in management of hypercalcemia in parathyroid carcinoma include plicamycin or mithramycin, octreotide and gallium nitrate [13,15,106e108]. Radiation therapy The general belief is that parathyroid carcinoma is usually a radio-resistant malignancy, with mainly disappointing results seen upon use of radiation therapy [14,19,38]. Therefore, the use of routine radiotherapy is not currently in practice. Only 9.8% of patients in the SEER study received radiation therapy. Its use did not change significantly during the 16-year study period and was not associated with an improved survival rate [4]. However, several single institution case series reported decreased recurrence in patients who received adjuvant radiation therapy [5,21,40,60,93,109]. Larger multi-centered randomized studies are required in order to reach results of statistical significance. Chemotherapy There is no evidence of effectiveness of chemotherapy in parathyroid carcinoma, and due to the rarity of this condition, experience is limited to case reports [1,5,8,40]. Chemotherapy is generally reserved for patients with inoperable disease, namely extensive local or metastatic disease, deemed unsuitable for surgical intervention. No standard protocol for treatment is currently available. Tested regimens including regimens containing nitrogen mustard; vincristine, cyclophosphamide, and actinomycin D; adriamycin, cyclophosphamide, and 5-fluorouracil; and adriamycin alone, were found to be ineffective [7]. Scattered case reports showed some benefit with regimens containing dacarbazine, either alone or in combination with other agents, such as fluorouracil and cyclophosphamide. [13,110], Due to the fact that there is no evidencebased data on the use of chemotherapy in parathyroid carcinoma, these results should be observed with caution. It is generally recommended that the decision to give chemotherapy should be individualized to each patient. Prognosis The prognosis of parathyroid cancer is variable, however, it is associated with a better overall survival rate than most solid tumors [5]. In a published study by Harari et al. [21], a median overall survival of 14.3 years was reported. In the NCDB study, where 286 cases of parathyroid carcinoma were analyzed, the overall 5 and 10year survival rates were found to be 85.5% and 49.1%, respectively [6]. In the SEER study, a review of 224 cases showed a higher 10year survival rate of 67.8% [4]. Similarly, Sandelin et al.

demonstrated a 10-year survival rate of 70% in a report of 95 patients from the Swedish Cancer Registry database [79]. Due to lack of effective adjuvant treatments, early identification and optimal resection of the tumor at the time of primary surgery offers the best prognostic chance [2,23,79]. Disease recurrence occurs in at least 50% of the cases, and is usually indicated by elevated serum calcium and PTH on follow-up laboratory tests [2,5,21,40]. The most common site of recurrence is the neck, and the standard treatment is surgical resection when technically feasible. In fact, many patients eventually require several surgical procedures during the course of their disease. The mean time from the initial surgery to recurrence ranges from 2.5 to 4.8 years, however recurrent cases have been reported with a latency of up to 23 years [2,5,21]. The eventual cause of death in patients with recurrent or metastatic parathyroid carcinoma is most commonly secondary to effects of chronic intractable hypercalcemia, and not due to the tumor bulk itself [2,5,15]. In a publication by Koea and Shaw [19], adverse prognostic factors for survival were shown to include the performance of simple parathyroidectomy as the initial procedure, the presence of nodal or distant metastatic disease at presentation, and a diagnosis of nonfunctioning parathyroid carcinoma. Harari et al. also identified a negative prognostic association in patients with an increased number of recurrences, higher calcium level at recurrence, and a high number of calcium-lowering medications [21]. There is controversy on whether or not the presence of positive regional lymph nodes affects prognosis. Two of the largest studies on parathyroid carcinoma, the SEER study and the NCDB study [4,6], demonstrated no influence of lymph node status on prognosis. However, Harari’s study on 37 patients did find that lymph node status was a prognostic indicator of mortality [21]. It also should be noted that both the SEER study and the NCDB study showed no association between tumor size and prognosis. As reported by the SEER study, young age, recent year of diagnosis (i.e. tumors diagnosed in the later years of the study), and female gender positively affected overall survival rate [4]. Conclusion Parathyroid carcinoma is an extremely rare endocrine malignancy, which typically presents with the clinical sequelae of extremely elevated serum calcium levels. At least one preoperative imaging study is recommended to accurately localize the tumor. FNA biopsies however should be avoided. The primary modality of treatment is surgical en-block resection of the tumor and any involved surrounding structures. There is no evidence of effectiveness of adjuvant chemo- or radiotherapy, however some data indicate their usefulness and therapy should be tailored to the individual patient. Parathyroid carcinoma is typically associated with a prolonged clinical course, with multiple recurrences e the majority of which occur locally. Due to limited value of adjuvant therapies, the recommended treatment for recurrences and metastases is also surgical resection, when technically feasible. Further multi-centric studies are required in order to further understand this rare clinical entity, and to develop more effective treatment methods. Conflict of interest statement The authors report no financial or ethical conflicts of interest. Authorship statement Guarantor of the integrity of the study: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh

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Study concepts: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Study design: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Definition of intellectual content: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Literature research: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Data acquisition: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Data analysis: Abbas Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Manuscript preparation: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Manuscript editing: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh Manuscript review: Abbas Al-Kurd, Michal Mekel, Haggi Mazeh

References

[26]

[27]

[28]

[29]

[30] [31]

[1] Dudney WC, Bodenner D, Stack Jr BC. Parathyroid carcinoma. Otolaryngol Clin North Am 2010;43:441e53. xi. [2] Kebebew E, Arici C, Duh QY, Clark OH. Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg 2001;136: 878e85. [3] Kebebew E. Parathyroid carcinoma. Curr Treat Options Oncol 2001;2: 347e54. [4] Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109: 1736e41. [5] Wei CH, Harari A. Parathyroid carcinoma: update and guidelines for management. Curr Treat Options Oncol 2012;13:11e23. [6] Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985-1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1999;86: 538e44. [7] de Quevain F. Parastruma maligna aberrata. Dtsch Z Fuer Chir 1904;100: 334e52. [8] Givi B, Shah JP. Parathyroid carcinoma. Clin Oncol R Coll Radiol 2010;22: 498e507. [9] Ruda JM, Hollenbeak CS, Stack Jr BC. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005;132:359e72. [10] Jarman WT, Myers RT, Marshall RB. Carcinoma of the parathyroid. Arch Surg 1978;113:123e5. [11] Obara T, Fujimoto Y. Diagnosis and treatment of patients with parathyroid carcinoma: an update and review. World J Surg 1991;15:738e44. [12] Clark P, Wooldridge T, Kleinpeter K, Perrier N, Lovato J, Morton K. Providing optimal preoperative localization for recurrent parathyroid carcinoma: a combined parathyroid scintigraphy and computed tomography approach. Clin Nucl Med 2004;29:681e4. [13] Mohebati A, Shaha A, Shah J. Parathyroid carcinoma: challenges in diagnosis and treatment. Hematol/Oncol Clin North Am 2012;26:1221e38. [14] Thompson SD, Prichard AJ. The management of parathyroid carcinoma. Curr Opin Otolaryngol Head Neck Surg 2004;12:93e7. [15] Shane E. Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab 2001;86:485e93. [16] Ireland JP, Fleming SJ, Levison DA, Cattell WR, Baker LR. Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck. J Clin Pathol 1985;38:1114e8. [17] Mashburn MA, Chonkich GD, Chase DR, Petti Jr GH. Parathyroid carcinoma: two new casesediagnosis, therapy, and treatment. Laryngoscope 1987;97: 215e8. [18] Christmas TJ, Chapple CR, Noble JG, Milroy EJ, Cowie AG. Hyperparathyroidism after neck irradiation. Br J Surg 1988;75:873e4. [19] Koea JB, Shaw JH. Parathyroid cancer: biology and management. Surg Oncol 1999;8:155e65. [20] Khan MW, Worcester EM, Straus 2nd FH, Khan S, Staszak V, Kaplan EL. Parathyroid carcinoma in secondary and tertiary hyperparathyroidism. J Am Coll Surg 2004;199:312e9. [21] Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E, et al. Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab 2011;96:3679e86. [22] Goldfarb M, O’Neal P, Shih JL, Hartzband P, Connolly J, Hasselgren PO. Synchronous parathyroid carcinoma, parathyroid adenoma, and papillary thyroid carcinoma in a patient with severe and long-standing hyperparathyroidism. Endocr Pract 2009;15:463e8. [23] Kebebew E. Parathyroid carcinoma, a rare but important disorder for endocrinologists, primary care physicians, and endocrine surgeons. Thyroid 2008;18:385e6. [24] Sharretts JM, Simonds WF. Clinical and molecular genetics of parathyroid neoplasms. Best Pract Res Clin Endocrinol Metab 2010;24:491e502. [25] Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ. Familial isolated hyperparathyroidism is rarely caused by germline mutation in

[32]

[33] [34]

[35]

[36]

[37] [38]

[39] [40]

[41]

[42] [43] [44]

[45]

[46] [47]

[48]

[49]

[50] [51] [52]

[53] [54] [55] [56]

7

HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004;89:96e102. Haven CJ, van Puijenbroek M, Tan MH, Teh BT, Fleuren GJ, van Wezel T, et al. Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clin Endocrinol (Oxf) 2007;67:370e6. Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, BaileyWilson J, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002;32:676e80. Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 2004;89:5583e91. Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Salenave S, et al. Frequent large germline HRPT2 deletions in a French national cohort of patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2013;98:E403e8. Kutcher MR, Rigby MH, Bullock M, Trites J, Taylor SM, Hart RD. Hyperparathyroidism-jaw tumor syndrome. Head Neck 2013;35:E175e7. Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349:1722e9. Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet 2003;40:657e63. Sharretts JM, Kebebew E, Simonds WF. Parathyroid cancer. Semin Oncol 2010;37:580e90. Kim HK, Oh YL, Kim SH, Lee DY, Kang HC, Lee JI, et al. Parafibromin immunohistochemical staining to differentiate parathyroid carcinoma from parathyroid adenoma. Head Neck 2012;34:201e6. Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery Jr AL, et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 1994;330:757e61. Shattuck TM, Kim TS, Costa J, Yandell DW, Imanishi Y, Palanisamy N, et al. Mutational analyses of RB and BRCA2 as candidate tumour suppressor genes in parathyroid carcinoma. Clin Endocrinol (Oxf) 2003;59:180e9. Cryns VL, Rubio MP, Thor AD, Louis DN, Arnold A. p53 abnormalities in human parathyroid carcinoma. J Clin Endocrinol Metab 1994;78:1320e4. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Med Baltim 1992;71: 197e205. Rao SR, Shaha AR, Singh B, Rinaldo A, Ferlito A. Management of cancer of the parathyroid. Acta Oto-laryngologica 2002;122:448e52. Busaidy NL, Jimenez C, Habra MA, Schultz PN, El-Naggar AK, Clayman GL, et al. Parathyroid carcinoma: a 22-year experience. Head Neck 2004;26: 716e26. Levin KE, Galante M, Clark OH. Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia. Surgery 1987;101: 649e60. Holmes EC, Morton DL, Ketcham AS. Parathyroid carcinoma: a collective review. Ann Surg 1969;169:631e40. Shane E, Bilezikian JP. Parathyroid carcinoma: a review of 62 patients. Endocr Rev 1982;3:218e26. Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia, and carcinoma: localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. Surg Oncol Clin N Am 1998;7:721e48. Schoretsanitis G, Daskalakis M, Melissas J, Tsiftsis DD. Parathyroid carcinoma: clinical presentation and management. Am J Otolaryngol 2009;30: 277e80. Messerer CL, Bugis SP, Baliski C, Wiseman SM. Normocalcemic parathyroid carcinoma: an unusual clinical presentation. World J Surg Oncol 2006;4:10. Campenni A, Ruggeri RM, Sindoni A, Giovinazzo S, Calbo E, Ieni A, et al. Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism. J Bone Miner Metab 2012;30:367e72. Piciu D, Irimie A, Kontogeorgos G, Piciu A, Buiga R. Highly aggressive pathology of non-functional parathyroid carcinoma. Orphanet J Rare Diseases 2013;8:115. Wilkins BJ, Lewis Jr JS. Non-functional parathyroid carcinoma: a review of the literature and report of a case requiring extensive surgery. Head Neck Pathol 2009;3:140e9. Gao WC, Ruan CP, Zhang JC, Liu HM, Xu XY, Sun YP, et al. Nonfunctional parathyroid carcinoma. J Cancer Res Clin Oncol 2010;136:969e74. Mazeh H, Prus D, Freund HR. Incidental non-functional parathyroid carcinoma identified during thyroidectomy. Isr Med Assoc J 2008;10:659. Fujimoto Y, Obara T, Ito Y, Kodama T, Nobori M, Ebihara S. Localization and surgical resection of metastatic parathyroid carcinoma. World J Surg 1986;10:539e47. Okamoto T, Iihara M, Obara T, Tsukada T. Parathyroid carcinoma: etiology, diagnosis, and treatment. World J Surg 2009;33:2343e54. Yamamoto T, Matsumura A. Comment on “Clinical review 122: parathyroid carcinoma”. J Clin Endocrinol Metab 2001;86:5091. Talat N, Schulte KM. Clinical presentation, staging and long-term evolution of parathyroid cancer. Ann Surg Oncol 2010;17:2156e74. Schaapveld M, Jorna FH, Aben KK, Haak HR, Plukker JT, Links TP. Incidence and prognosis of parathyroid gland carcinoma: a population-based study in

Please cite this article in press as: Al-Kurd A, et al., Parathyroid carcinoma, Surgical Oncology (2014), http://dx.doi.org/10.1016/ j.suronc.2014.03.005

8

A. Al-Kurd et al. / Surgical Oncology xxx (2014) 1e8

[57]

[58]

[59]

[60] [61]

[62] [63] [64]

[65] [66] [67]

[68] [69]

[70] [71] [72] [73] [74] [75] [76]

[77] [78] [79] [80] [81]

[82]

[83] [84]

The Netherlands estimating the preoperative diagnosis. Am J Surg 2011;202: 590e7. Rubin MR, Bilezikian JP, Birken S, Silverberg SJ. Human chorionic gonadotropin measurements in parathyroid carcinoma. Eur J Endocrinol 2008;159: 469e74. Silverberg SJ, Shane E, Jacobs TP, Siris ES, Gartenberg F, Seldin D, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990;89:327e34. Patel CN, Salahudeen HM, Lansdown M, Scarsbrook AF. Clinical utility of ultrasound and 99mTc sestamibi SPECT/CT for preoperative localization of parathyroid adenoma in patients with primary hyperparathyroidism. Clin Radiol 2010;65:278e87. Sandelin K. Parathyroid carcinoma. Philadelphia: Elsevier Saunders; 2005. Reeder SB, Desser TS, Weigel RJ, Jeffrey RB. Sonography in primary hyperparathyroidism: review with emphasis on scanning technique. J Ultrasound Med Off J Am Inst Ultrasound Med 2002;21:539e52. quiz 53e4. Solbiati L, Osti V, Cova L, Tonolini M. Ultrasound of thyroid, parathyroid glands and neck lymph nodes. Eur Radiol 2001;11:2411e24. Tamler R, Lewis MS, LiVolsi VA, Genden EM. Parathyroid carcinoma: ultrasonographic and histologic features. Thyroid 2005;15:744e5. Sidhu PS, Talat N, Patel P, Mulholland NJ, Schulte KM. Ultrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm. Eur Radiol 2011;21:1865e73. Rodgers SE, Perrier ND. Parathyroid carcinoma. Curr Opin Oncol 2006;18: 16e22. Al-Sobhi S, Ashari LH, Ingemansson S. Detection of metastatic parathyroid carcinoma with Tc-99m sestamibi imaging. Clin Nucl Med 1999;24:21e3. Evangelista L, Sorgato N, Torresan F, Boschin IM, Pennelli G, Saladini G, et al. FDG-PET/CT and parathyroid carcinoma: review of literature and illustrative case series. World J Clin Oncol 2011;2:348e54. Kassahun WT, Jonas S. Focus on parathyroid carcinoma. Int J Surg 2011;9: 13e9. Spinelli C, Bonadio AG, Berti P, Materazzi G, Miccoli P. Cutaneous spreading of parathyroid carcinoma after fine needle aspiration cytology. J Endocrinol Invest 2000;23:255e7. Owen RP, Silver CE, Pellitteri PK, Shaha AR, Devaney KO, Werner JA, et al. Parathyroid carcinoma: a review. Head Neck 2011;33:429e36. Clark O. Parathyroid carcinoma. Michigan: McGraw-Hill Companies; 2006. Fujimoto Y, Obara T. How to recognize and treat parathyroid carcinoma. Surg Clin North Am 1987;67:343e57. Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinoma. Am J Surg Pathol 1993;17:820e9. Schantz A, Castleman B. Parathyroid carcinoma. A study of 70 cases. Cancer 1973;31:600e5. Smith JF, Coombs RR. Histological diagnosis of carcinoma of the parathyroid gland. J Clin Pathol 1984;37:1370e8. Obara T, Okamoto T, Kanbe M, Iihara M. Functioning parathyroid carcinoma: clinicopathologic features and rational treatment. Semin Surg Oncol 1997;13:134e41. Shaha AR, Shah JP. Parathyroid carcinoma: a diagnostic and therapeutic challenge. Cancer 1999;86:378e80. Schulte KM, Gill AJ, Barczynski M, Karakas E, Miyauchi A, Knoefel WT, et al. Classification of parathyroid cancer. Ann Surg Oncol 2012;19:2620e8. Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO. Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg 1992;16:724e31. Rawat N, Khetan N, Williams DW, Baxter JN. Parathyroid carcinoma. Br J Surg 2005;92:1345e53. Enomoto K, Uchino S, Ito A, Watanabe S, Shibuya H, Enomoto Y, et al. The surgical strategy and the molecular analysis of patients with parathyroid cancer. World J Surg 2010;34:2604e10. Rubello D, Mariani G, Pelizzo MR, Italian Study Group of Radioguided S, ImmunoScintigraphy. Minimally invasive radio-guided parathyroidectomy on a group of 452 primary hyperparathyroid patients: refinement of preoperative imaging and intraoperative procedure. Nukl Nucl Medicine 2007;46:85e92. Chen H. Radioguided parathyroid surgery. Adv Surg 2004;38:377e92. Chen H, Mack E, Starling JR. Radioguided parathyroidectomy is equally effective for both adenomatous and hyperplastic glands. Ann Surg 2003;238: 332e7 [discussion 7e8].

[85] Chen H, Sippel RS, Schaefer S. The effectiveness of radioguided parathyroidectomy in patients with negative technetium tc 99m-sestamibi scans. Arch Surg 2009;144:643e8. [86] Placzkowski K, Christian R, Chen H. Radioguided parathyroidectomy for recurrent parathyroid cancer. Clin Nucl Med 2007;32:358e60. [87] Cavalier E, Daly AF, Betea D, Pruteanu-Apetrii PN, Delanaye P, Stubbs P, et al. The ratio of parathyroid hormone as measured by third- and secondgeneration assays as a marker for parathyroid carcinoma. J Clin Endocrinol Metab 2010;95:3745e9. [88] Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. Surgery 2005;138:583e7 [discussion 7e90]. [89] Oh MY, Oh SB, Seoung HG, Kim JH, Kim SS, Kim BH, et al. Concurrent parathyroid carcinoma and hyperplasia in hyperparathyroidism. Korean J Intern Med 2012;27:356e9. [90] Kauffmann RM, Juhlin CC, Fohn LE, Broome JT, Phay JE. Parathyroid carcinoma arising from four-gland hyperplasia. Endocr Pract 2011;17:e37e42. [91] Hoelting T, Weber T, Werner J, Herfarth C. Surgical treatment of parathyroid carcinoma (Review). Oncol Rep 2001;8:931e4. [92] Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur J Endocrinol 2013;168:R45e53. [93] Munson ND, Foote RL, Northcutt RC, Tiegs RD, Fitzpatrick LA, Grant CS, et al. Parathyroid carcinoma: is there a role for adjuvant radiation therapy? Cancer 2003;98:2378e84. [94] Shaha AR, Ferlito A, Rinaldo A. Distant metastases from thyroid and parathyroid cancer. ORL; J Oto-rhino-laryngology Its Related Specialties 2001;63: 243e9. [95] Yoshida S. Intracranial metastatic parathyroid carcinoma: case report. Surg Neurol 2006;65:81e3. [96] Kern M, Lee G, Robbins P, Bynevelt M, Watson P. Intracranial metastatic parathyroid carcinoma. Case report and review of the literature. J Neurosurg 2004;101:1065e9. [97] Kar DK, Mishra A, Mishra SK. Brain metastasis from parathyroid carcinoma. J Assoc Physicians India 2003;51:68e70. [98] Lumachi F, Basso SM, Basso U. Parathyroid cancer: etiology, clinical presentation and treatment. Anticancer Res 2006;26:4803e7. [99] Mann K. Oral biphosphonate therapy in metastatic parathyroid carcinoma. Lancet 1985;1:101e2. [100] Jacobs TP, Gordon AC, Silverberg SJ, Shane E, Reich L, Clemens TL, et al. Neoplastic hypercalcemia: physiologic response to intravenous etidronate disodium. Am J Med 1987;82:42e50. [101] Silverberg SJ, Rubin MR, Faiman C, Peacock M, Shoback DM, Smallridge RC, et al. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab 2007;92:3803e8. [102] Peacock M, Bilezikian JP, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, et al. Cinacalcet HCl reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity. J Clin Endocrinol Metab 2011;96:E9e18. [103] Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90:135e41. [104] Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med 2004;32:S146e54. [105] Martrat G, Maxwell CA, Tominaga E, Porta M, Bonifaci N, Gomez-Baldo L, et al. Exploring the link between MORF4L1 and risk of breast cancer. Breast Cancer Res 2011;13:R40. [106] Denney AM, Watts NB. The effect of octreotide on parathyroid carcinoma. J Clin Endocrinol Metab 2004;89:1016. [107] Koyano H, Shishiba Y, Shimizu T, Suzuki N, Nakazawa H, Tachibana S, et al. Successful treatment by surgical removal of bone metastasis producing PTH: new approach to the management of metastatic parathyroid carcinoma. Intern Med 1994;33:697e702. [108] Warrell Jr RP, Issacs M, Alcock NW, Bockman RS. Gallium nitrate for treatment of refractory hypercalcemia from parathyroid carcinoma. Ann Intern Med 1987;107:683e6. [109] Chow E, Tsang RW, Brierley JD, Filice S. Parathyroid carcinomaethe Princess Margaret hospital experience. Int J Radiat Oncol Biol Phys 1998;41:569e72. [110] Bukowski RM, Sheeler L, Cunningham J, Esselstyn C. Successful combination chemotherapy for metastatic parathyroid carcinoma. Arch Intern Med 1984;144:399e400.

Please cite this article in press as: Al-Kurd A, et al., Parathyroid carcinoma, Surgical Oncology (2014), http://dx.doi.org/10.1016/ j.suronc.2014.03.005