Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Immunocyte density in parathyroid carcinoma is correlated with disease relapse.

PURPOSE: Parathyroid carcinoma (PC) is an endocrine malignancy with a poor prognosis. The tumour immune microenvironment is a critical factor influencing the outcomes of multiple cancer types. However, knowledge of the immune microenvironment in PC remains limited. METHODS: The intratumoural density of immunocytes and the Ki-67 index were evaluated immunohistochemically in 51 PC patient samples and were compared with clinicopathological features and parafibromin staining results. The Kaplan-Meier method and Cox proportional hazards analysis were used to estimate the effects of these variables on clinical outcomes. RESULTS: Intratumoural immunocyte density was not correlated with age, gender, urolithiasis, or palpation of a neck mass. The Ki-67 index was correlated with the intratumoural density of CD3+ cells (P = 0.022) and CD8+ cells (P = 0.021) and serum calcium levels (P = 0.022). In the intratumoural area of primary foci, Kaplan-Meier method showed that the risk factors associated with recurrence/metastasis were a low density of CD3+ (P = 0.017), CD8+ (P = 0.019) and CD45+ cells (P = 0.047), a high density of CD163+ cells (P = 0.003) and a high Ki-67 index (P = 0.004). Cox regression multivariate analysis revealed that CD163+ cell density (hazard ratio (HR) 16.19, 95% confidence interval (CI) 1.99-131.66; P = 0.009) and CD8+ cell density (HR 0.13, 95% CI 0.02-0.76, P = 0.024) were independent factors associated with PC relapse. CONCLUSION: The immune microenvironment is an important factor influencing the relapse of PC. The intratumoural density of CD3+, CD8+, CD45+, and CD163+ immunocytes was correlated with disease-free survival (DFS) in patients with PC. Immunotherapy based on T lymphocytes or tumour-associated macrophages may be a promising treatment strategy.

Risk of Distant Metastasis in Parathyroid Carcinoma and Its Effect on Survival: A Retrospective Review from a High-Volume Center.

BACKGROUND: Development of distant metastases (DM) is associated with markedly decreased survival in parathyroid carcinoma (PC). We sought to identify factors associated with development of DM and to quantify the effect that development of DM had on overall survival (OS). METHODS: Patients with surgically resected local/regional PC treated or surveilled at a tertiary-referral cancer hospital from 1980 to 2017 were included. We assessed the association between biochemical and clinicopathologic factors (preoperative parathyroid hormone (PTH) levels, sex, race, age, preoperative serum calcium levels, serum calcium levels at 6 months postop, tumor size, and extent of resection) with the development of DM. We also assessed the effect of development of DM on OS. RESULTS: Seventy-five patients with PC were assessed; 17 (22.7%) developed DM at a median follow-up of 77 months. The cumulative incidence of DM in the cohort was 20, 30, and 38% at 5, 10, and 20 years respectively. Tumor size > 3.2 cm based on recursive partitioning analysis was the only significant predictor for development of DM (hazard ratio (HR) = 3.51; 95% confidence interval [CI] 1.04-11.91; p = 0.04). Median OS for the entire cohort was 17 years compared with 40 months for the cohort who developed DM. The HR for death after distant metastasis was 9.6 (95% CI 4.2-22.3; p < 0.0001). CONCLUSIONS: Development of distant metastasis during surveillance is associated with decreased OS, including late recurrences. Primary tumor size should be considered in future interval surveillance and development of treatment algorithms.

Tumor Size and Presence of Metastatic Disease at Diagnosis are Associated with Disease-Specific Survival in Parathyroid Carcinoma.

BACKGROUND: The incidence of parathyroid carcinoma is reported to be rising. There is minimal data on prognostic variables associated with cancer-specific survival. The objectives of this study were to evaluate the trends in incidence and assess prognostic factors. METHODS: A retrospective review of the SEER database between 1973 and 2014 was performed, identifying 520 patients with parathyroid carcinoma. Population-adjusted incidence rates were calculated in 4-year intervals. A Cochrane-Armitage test was performed to analyze changes in trend in incidence, tumor size, and extent of disease. Age, year of diagnosis, race, gender, extent of disease, surgical resection, treatment with radiation, tumor size, and lymph node status were assessed using Mantel-Cox log rank test. Multivariate analysis was performed by Cox regression analysis. RESULTS: The incidence of parathyroid carcinoma has been increasing since 1974 from 2 to 11 cases per 10 million people but has since stabilized at 11 cases per 10 million people since 2001. The increasing incidence was attributed to locoregional disease and tumor size < 3 cm. The presence of metastatic disease [hazard ratio (HR) 111.4, 95% confidence interval (CI) 20.6-601.8, p < 0.0001) and tumor size > 3 cm (HR 5.6, 95% CI 1.5-21.2, p = 0.011] were associated with worse cancer-specific survival by univariate and multivariate analyses. CONCLUSIONS: The incidence of parathyroid carcinoma has remained stable over the past decade. Tumor size < 3 cm and regional disease have increased in incidence. Patients with metastatic disease and tumors > 3 cm have worse cancer-specific survival. These findings can be incorporated in the development of a staging system for parathyroid carcinoma.

Parathyroid Hormone Levels Predict Long-Term Outcome After Operative Management of Parathyroid Cancer.

The role of parathyroid hormone (PTH) serum levels for prediction of outcome is ill defined for parathyroid cancer, which is a very rare disease. This investigation of 17 consecutive patients with parathyroid cancer, (re-)operated on at a tertiary referral center between 1994 and July 2016, with a mean follow-up of 179.6 months (15 years) aimed to clarify the suitability of PTH serum levels for prediction of clinical outcome after comprehensive operative management of parathyroid cancer. Cancer-specific mortality occurred significantly more often with the performance of sternotomy before or at first operation at this institution (80 vs. 0%; p=0.002); mean PTH serum levels before first operation (1 105 vs. 357 pg/ml; p=0.008; r=0.77) and at most recent follow-up (3 167 vs. 101 pg/ml; p=0.019; r=0.60); and normalization of PTH serum levels at most recent follow-up (0 vs. 64%; p=0.034). For cancer-specific survival, receiver-operating characteristics analysis identified as optimum cut-off point an initial PTH serum level of 700 pg/ml. For local recurrence, no significant associations were found. Kaplan-Meier analysis confirmed that the patients with initial PTH serum levels >700 pg/ml (plog-rank=0.011) and sternotomy (plog-rank<0.001), but not node or lung metastases, had worse cancer-specific survival. Parathyroid cancer is much more an endocrine disease with oncological features than an oncological disease with endocrine features. Operative intervention(s) should be comprehensive and directed at clearing all metabolically active parathyroid tumor deposits early. If surgical cure cannot be reached, it is pivotal to achieve metabolic control, obviating the need for, or facilitating, medical therapy of hypercalcemia, and preserve renal function.

The Incidence and Survival of Rare Cancers of the Thyroid, Parathyroid, Adrenal, and Pancreas.

PURPOSE: With the exception of papillary and follicular thyroid cancer, malignant cancers of the thyroid, parathyroid, adrenal, and endocrine pancreas are uncommon. These rare malignancies present a challenge to both the clinician and patient, because few data exist on their incidence or survival. We analyzed the incidence and survival of these rare endocrine cancers (RECs), as well as the trends in incidence over time. METHODS: We used the NCI's SEER 18 database (2000-2012) to investigate incidence and survival of rare cancers of the thyroid, parathyroid, adrenal, and endocrine pancreas. Cancers were categorized using the WHO classification systems. We collected data on incidence, gender, stage, size, and survival. Time trends were evaluated from 2000-2002 to 2010-2012. RESULTS: We identified 36 types of rare cancers in the endocrine organs captured in the SEER database. RECs of the thyroid had the highest combined incidence rate (IR8.26), followed by pancreas (IR 3.24), adrenal (IR 2.71), and parathyroid (IR 0.41). The incidence rate for all rare endocrine organs combined increased 32.4 % during the study period. The majority of the increase was attributable to rare cancers of thyroid, which increased in not only microcarcinomas, but in all sizes. The mean 5-year survival for RECs is 59.56 % (range 2.49­100 %). CONCLUSIONS: This study is a comprehensive analysis ofthe incidence and survival for rare malignant endocrine cancers. There has been an increase in incidence rate of almost all RECs and their survival is low. We hope that our data will serve as a source of information for clinicians as well as bring awareness regarding these uncommon cancers.

Preoperative diagnosis and prognosis in 40 Parathyroid Carcinoma Patients.

OBJECTIVE: Parathyroid carcinoma (PC) is a rare disease which is difficult to diagnose preoperatively and predict prognosis. The goal of this study was to analyse the preoperative predictive factors and prognostic factors in PC patients and to evaluate the possibility of diagnosing PC preoperatively. DESIGN, SETTING AND PATIENTS: This is a retrospective study from Jan 2000 to Aug 2015 conducted in Shanghai Ruijin Hospital. MEASUREMENTS: Comparisons were made between 40 parathyroid carcinoma patients and 282 patients with benign parathyroid lesions during the same period. All patients underwent parathyroid surgery, and the results were certified by paraffin pathology. Prognostic factors were analysed in the 40 PC patients. RESULTS: Patients with higher levels of intact parathyroid hormone (P < 0·001, OR = 1·001, CI: 1·000-1·002), calcium (P = 0·008, OR = 3·395, CI: 1·382-8·341) and a larger parathyroid volume (P = 0·001, OR = 2·023, CI: 1·333-3·071) were more likely to have PC. Local excision (P = 0·008, OR = 4·992, CI: 1·533-16·252), stage III in the Schulte staging system (P = 0·039, OR = 9·600, CI: 1·12-82·322), high risk in the Schulte Risk Classification (P = 0·012, OR = 5·466, CI: 1·448-20·628) and first surgery by other medical teams (P = 0·008, OR = 4·992, CI: 1·496-15·037) were associated with PC recurrence. Calcium (P = 0·01, OR = 7·270, CI: 1·611-32·812), intact parathyroid hormone (P = 0·037, OR = 1·001, CI: 1·000-1·001), local excision (P = 0·009, OR = 6·875, CI: 1·633-28·936) and recurrence (P = 0·014, OR = 7·762, CI: 1·504-40·055) were associated with death. CONCLUSIONS: A preoperative diagnostic system may provide a new method to distinguish PC from benign parathyroid lesions before surgery. For PC patients who did not undergo en-bloc resection at first operation, timely further surgery may offer a second chance of cure. Early diagnosis and surgery are pivotal to reduce mortality in PC patients.

Oncologic progress for the treatment of parathyroid carcinoma is needed.

BACKGROUND AND OBJECTIVES: Parathyroid carcinoma (PC) is rare but potentially lethal. No standardized staging system or treatment guidelines have been established. We aimed to determine whether management of PC and patient outcomes have changed at our institution over the past 35 years. METHODS: Retrospective review of patients with PC at our institution between 1980 and 2015. Patients were grouped by date of initial surgery: group 1, 1980-2001; group 2, 2002-2015. RESULTS: About 57 patients (26 in group 1; 31 in group 2) were included. Group 2 had more female patients (61%) than group 1 (31%; P = 0.033). Patients in group 2 were older at the time of initial operation (mean age 48 years in group 1 (SD:14.3) and 56 years (SD:14.6) in group 2; P = 0.034). The 5-year OS rates were 82% (95%CI 59.6%, 93%) for group 1 and 72% (95%CI 45.0%, 87.7%) for group 2. The 5-year DFS rates were 62% (95%CI 36.4%, 79.9%) for group 1 and 66% (95%CI 40.6%, 82.2%) for group 2. CONCLUSION: Management of PC and patient outcomes (OS and DFS) have not significantly changed over the past 35 years at our institution. This rare malignancy needs oncologic improvement. J. Surg. Oncol. 2016;114:708-713. © 2016 Wiley Periodicals, Inc.

Parathyroid Carcinoma: An Update on Treatment Outcomes and Prognostic Factors from the National Cancer Data Base (NCDB).

BACKGROUND: Parathyroid carcinoma is a rare disease. Conflicting results on prognostic factors and extent of surgical resection for patients with parathyroid carcinoma have been made based on small sample sizes. A large, robust dataset is needed to help address some of the controversies. METHODS: A retrospective review of patients with parathyroid carcinoma in the National Cancer Data Base from 1985 to 2006 was performed. Characteristics of the cohort and type of treatment were evaluated. Prognostic factors were assessed with Cox proportional hazards regression models and 5- and 10-year OS rates were determined. RESULTS: There were 733 evaluable patients with a mean age of 56.1 ± 15.3 years (median 57, range 15-89) and mean tumor size of 29.6 ± 18.4 mm (median 25.0 mm, range 10.0-150.0). Tumor size, age at diagnosis, male sex, positive nodal status, and complete tumor resection had hazard ratios for death of 1.02 (1.01-1.02, p < 0.0001), 1.06 (1.05-1.07, p < 0.0001), 1.67 (1.24-2.25, p = 0.0008), 1.25 (0.57-2.76, p = 0.6), and 0.42 (0.22-0.81, p = 0.01), respectively, on multivariable analysis. Patients who had removal of the parathyroid tumor with concomitant resection of adjacent organs had HR for death of 0.70 (0.35-1.41, p = 0.3). The 5- and 10-year OS rates were 82.3 and 66 % respectively. CONCLUSIONS: Patient age, tumor size, and sex have modest effects on survival in patients with parathyroid carcinoma. A staging system with prognostic value for parathyroid carcinoma should include at least these pertinent prognostic factors.

Oncologic resection achieving r0 margins improves disease-free survival in parathyroid cancer.

BACKGROUND: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. METHODS: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ (2) testing and Kaplan-Meier statistics. RESULTS: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ (2) = 5.6; p < 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (χ (2) = 8.1; p < 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (χ (2) = 7.9; p = 0.005 and χ (2) = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients. CONCLUSIONS: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence.

The impact of surgical volume on racial disparity in thyroid and parathyroid surgery.

PURPOSE: The aim of this study was to evaluate the association between surgeon volume and patient outcomes among different race ethnicities undergoing thyroid or parathyroid surgery. METHODS: The nationwide inpatient sample was used to identify all thyroidectomy and parathyroidectomy admissions from 2003 to 2009, using International Classification of Diseases, 9th Clinical Modification (ICD-9-CM) procedure codes. Race, demographic, and clinical characteristics of patients were collected, along with surgeon volume, to predict the length of stay (LOS), complication rates, mortality, and total charges by racial group, using univariate and multivariate analyses. RESULTS: A total of 106,314 thyroid and parathyroid surgeries were included in the current analysis. Of these patients, 54 % were Caucasian, 11 % African American, 7 % Hispanic, and 3 % Asian. Mean LOS was longer for African American patients (4 ± 8.7 days) than for Caucasians (2.3 ± 5.5 days) [p < 0.001]. African Americans had higher overall complications (16.8 %) compared with Caucasians (11 %), Hispanics (13.5 %), and Asians (12 %) [p < 0.001]. In-hospital mortality was higher for African Americans (0.8 %) compared with that from other race groups (0.3 %) [p < 0.001]. Mean total charges were significantly higher for African Americans ($33,292 ± $67,387) compared with those for Caucasians ($22,855 ± $40,167) (p < 0.001). African Americans had less access to intermediate- (10-99 cases) and high- (>100 cases) volume surgeons compared with Caucasians-45 versus 49 %, and 16 versus 19 %, respectively (p < 0.001). Higher surgeon volume was associated with improved outcomes (p < 0.001). Racial disparity in all investigated outcomes was still significantly evident even after stratification by surgeon volume. CONCLUSION: Higher surgeon volume is associated with improved patient outcomes. However, our data suggests that the observed racial disparities in thyroid and parathyroid surgery go beyond access to quality healthcare providers.

Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas.

BACKGROUND: The histopathological criteria for carcinoma proposed by the World Health Organization (WHO) are imperfect predictors of the malignant potential of parathyroid tumors. Negative parafibromin (PF) and positive protein gene product 9.5 (PGP9.5) staining are markers of CDC73 mutation and occur commonly in carcinoma but rarely in adenomas. We investigated whether PF and PGP9.5 staining could be used to predict the behavior of atypical parathyroid adenomas--tumors with atypical features that do not fulfill WHO criteria for malignancy. METHODS: Long-term outcomes were compared across four groups: group A, WHO-positive criteria/PF-negative staining; group B, WHO(+)/PF(+), group C; WHO(-)/PF(-); and group D, WHO(-)/PF(+). RESULTS: Eighty-one patients were included in the period 1999-2012: group A (n = 13), group B (n = 14), group C (n = 21), and group D (n = 33). Mortality and recurrence rates, respectively, for group A were 15 and 38%, for group B 7 and 36%, for group C 0 and 10%, and for group D 0 and 0%. The PGP9.5(+) ratios for groups A to D were 85, 78, 71, and 12%, further informing prognosis. Five-year disease-free survival for groups A to D were 55, 80, 78, and 100%, respectively. Tumor recurrence was significantly associated with PF (p = 0.048) and PGP9.5 (p = 0.003) staining. CONCLUSIONS: Although WHO criteria are essential to differentiate parathyroid carcinoma from benign tumors, the presence of negative PF staining in an atypical adenoma predicts outcome better, whereas PF-positive atypical adenomas do not recur and can be considered benign. PF-negative atypical adenomas have a low but real recurrence risk and should be considered tumors of low malignant potential.

Classification of parathyroid cancer.

PURPOSE: Parathyroid cancer is rare and often has a poor outcome. There is no classification system that permits prediction of outcome in patients with parathyroid cancer. This study was designed to validate two prognostic classification systems developed by Talat and Schulte in 2010 ("Clinical Presentation, Staging and Long-term Evolution of Parathyroid Cancer," Ann Surg Oncol 2010;17:2156-74) derived from a retrospective literature review of 330 patients. METHODS: This study contains 82 formerly unreported patients with parathyroid cancer. Death due to disease was the primary end point, and recurrence and disease-free survival were the secondary end points. Data acquisition used a questionnaire of predefined criteria. Low risk was defined by capsular and soft tissue invasion alone; high risk was defined by vascular or organ invasion, and/or lymph node or distant metastasis. A differentiated classification system further classified high-risk cancer into vascular invasion alone (class II), lymph node metastasis or organ invasion (class III), and distant metastasis (class IV). Statistical analyses included risk analysis, Kaplan-Meier analysis, and receiver-operating characteristic (ROC) analysis. RESULTS: Follow-up ranged 2-347 months (mean 76 months). Mortality was exclusive to the high- risk group, which also predicted a significant risk of recurrence (risk ratio 9.6; 95% confidence interval 2.4-38.4; P < 0.0001), with significantly lower 5-year disease-free survival (χ(2) = 8.7; P < 0.005 for n = 45). The differentiated classification also provided a good prognostic model with an area under the ROC curve of 0.83 in ROC analysis, with significant impairment of survival between classes (98.6%, 79.2%, 71.4%, 40.0%, P < 0.05 between each class). CONCLUSIONS: This study confirms the validity of both classification systems for disease outcome in patients with parathyroid cancer.

Parathyroid carcinoma: update and guidelines for management.

Parathyroid carcinoma is one of the rarest known malignancies that may occur sporadically or as a part of a genetic syndrome. It accounts for approximately 1% of patients with primary hyperparathyroidism. The majority (90%) of parathyroid cancer tumors are hormonally functional and hypersecrete parathyroid hormone (PTH). Thus, most patients exhibit strong symptomatology of hypercalcemia at presentation. Sometimes, it can be difficult to diagnose parathyroid cancer preoperatively due to clinical features shared with benign causes of hyperparathyroidism. Imaging techniques such as neck ultrasound and 99mTc sestamibi scan can help localize disease, but they are not useful in the assessment of malignancy potential. Fine needle aspiration (FNA) prior to initial operation is not recommended due to technical difficulty in differentiating benign and malignant disease on cytology specimens and the possible associated risk of tumor seeding from the needle track. Complete surgical resection with microscopically negative margins is the recommended treatment and offers the best chance of cure. Persistent or recurrent disease occurs in more than 50% of patients with parathyroid carcinoma. Surgical resection is also the primary mode of therapy for recurrence since it can offer significant palliation for the metabolic derangement caused by hyperparathyroidism and allows hypercalcemia to become more medically manageable. However, reoperation is rarely curative and eventual relapse is likely. Chemotherapy and external beam radiation treatments have been generally ineffective in the treatment of parathyroid carcinoma. Typically, these patients require repeated operations that predispose them to accumulated surgical risks with each intervention. In inoperable cases, few palliative treatment options exist, although treatment with calcimimetics can effectively control hypercalcemia in some patients. Most patients ultimately succumb to complications of hypercalcemia rather than from tumor burden or infiltration.

Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma.

Parathyroid carcinoma is associated with mutations in the HRPT2/CDC73 gene and with decreased parafibromin and calcium-sensing receptor (CASR) expression, but in some cases establishing an unequivocal diagnosis remains a challenge. The aim of our study was to evaluate the prognostic value of CASR and parafibromin expression and of HRPT2/CDC73 mutations in patients with an established diagnosis of parathyroid carcinoma. Data on survival and disease-free survival were obtained from hospital records of 23 patients with an established diagnosis of parathyroid carcinoma in whom CASR and parafibromin expression and HRPT2/CDC73 mutation analyses were available from paraffin-embedded pathological specimens. Kaplan-Meier curves were used for survival analysis. Downregulation of CASR expression, global loss of parafibromin staining and a HRPT2/CDC73 mutation were, respectively, found in 7 (30%), 13 (59%) and 4 (17%) patients, and were associated with, respectively, 16-fold, 4-fold and 7-fold increased risk of developing local or distant metastasis. These findings suggest that although downregulation of CASR expression, global loss of parafibromin staining and mutations in the HRPT2/CDC73 gene are tools of proven value to assist in establishing a diagnosis of parathyroid carcinoma, their absence does not exclude it. Notwithstanding, we demonstrate a significant added value of these markers as strong determinants of increased malignant potential and thus as negative prognostic markers in this malignancy.

Clinical presentation, staging and long-term evolution of parathyroid cancer.

BACKGROUND: Parathyroid cancer is rare and often fatal. This review provides an in-depth analysis of 330 clinical cases reported in detail. These data are used to inform a proposal for a hitherto lacking TNM staging system. MATERIALS AND METHODS: All case reports or series with sufficient case details of parathyroid cancer were identified from PubMed, and data were analyzed using SPSS. RESULTS: Of 330 patients, 117 (35%) died of disease and 207 (63%) experienced recurrence in a total of 2007 follow-up years and a mean length of follow-up of 6.1 years. Histopathology findings rather than biochemical or clinical features predict outcome. In univariate analysis, survival and recurrence rates are significantly influenced by gender (male relative risk [RR] 1.7, 95% confidence interval [95% CI] 1.0-2.7, P < .01), and presence of vascular invasion (RR 4.3, 95% CI 1.1-17.7, P < .01), or lymph node metastases (RR 6.2, 95 %CI 0.9-42.9, P < .001). Failure to perform oncological surgery carries a high risk for recurrence and death (local versus en bloc resection RR 2.0, CI 1.2-3.2, P < .01) as for redo surgery. Staging by a novel anatomy-based TNM system identifies significant outcome variation as to recurrence and death. Separation of patients into low and high risk identifies a 3.5-7.0 fold higher risk of recurrence and death (P < .01) for the high-risk group. Distant metastases predominantly target mediastinum and lung. CONCLUSION: Understaging and undertreatment are shown to contribute to high recurrence rates and death toll. To improve outcome, en bloc resection including central lymph node dissection should be the minimal surgical approach in any patient with suspected parathyroid cancer.

Parathyroid carcinoma: etiology, diagnosis, and treatment.

BACKGROUND: The goal of the present study was to make our medical practice evidence-based for patients with parathyroid carcinoma. METHODS: We posed six clinical questions relevant to the management of parathyroid cancer. A comprehensive search and critical appraisal of the literature was then carried out. RESULTS: Most of the literature retrieved was retrospective in design and differed in the definition of carcinoma. The distinction between unequivocal and equivocal carcinoma (or atypical adenoma) was not always made for the study populations. None of the studies indicated reproducibility of outcome measures. Of the histopathological features described in the literature based on the description of Schantz and Castleman, capsular/vascular invasions and trabecular growth pattern were the most specific, and fibrous bands were the most sensitive. None of the patients with "atypical adenoma" developed recurrence, whereas 25% of those with "equivocal carcinoma" did. Mutations in HRPT2, the gene responsible for hereditary hyperparathyroidism with jaw-tumor syndrome, were strongly associated with sporadic parathyroid carcinoma. Severe hypercalcemia and its related clinical symptoms, extremely high levels of parathyroid hormone, osteitis fibrosa cystica, a palpable neck mass, and a relatively large depth-width ratio on ultrasonography, are the important features of parathyroid carcinoma. Disease-specific survival rates reported in the literature were varied, reflecting the differences in the definitions of carcinoma, study populations, and interventions. CONCLUSIONS: To establish valid evidence for patient management in the future, a collaboration of endocrine specialists is essential to conduct well-designed clinical studies for this rare disease.

Diagnostic and prognostic implications of parafibromin immunohistochemistry in parathyroid carcinomaT.

The aim of the present study was to elucidate the diagnostic and prognostic implications of parafibromin immunohistochemistry (IHC) in parathyroid carcinoma (PC). We performed a meta-analysis to examine the rate of loss of parafibromin expression from 18 eligible studies. In addition, a diagnostic test accuracy review was conducted to investigate the diagnostic role of parafibromin in PC. The rates of loss of parafibromin expression were 0.522 (95% CI: 0.444-0.599), 0.291 (95% CI: 0.207-0.391), 0.027 (95% CI: 0.011-0.064), and 0.032 (95% CI: 0.008-0.119) in PC, atypical parathyroid adenoma (APA), parathyroid adenoma (PA), and parathyroid hyperplasia, respectively. In the diagnostic test accuracy review for diagnosis of PC, the pooled sensitivity and specificity of parafibromin IHC was 0.53 (95% CI: 0.46-0.59) and 0.96 (95% CI: 0.95-0.97), respectively. The diagnostic odds ratio and the area under curve on summary receiver operating characteristic curve was 25.31 (95% CI: 8.91-71.87) and 0.7954, respectively. In addition, the meta-analysis demonstrated that loss of parafibromin expression was significantly correlated with worse disease-free survival (hazard ratio: 2.832; 95% CI: 1.081-7.421). Loss of parafibromin IHC expression was significantly higher in PC than in APA, PA, and parathyroid hyperplasia. Parafibromin IHC could be useful for diagnosis and prediction of prognosis of PC in daily practice.

[Parathyroid carcinoma: multicenter study of 17 patients]. / Carcinome parathyroïdien.

PURPOSE OF THE STUDY: To evaluate clinical characteristics and survival of patients treated for parathyroid carcinoma. STUDY DESIGN: A retrospective multicenter chart review of patients treated for parathyroid carcinoma between January 1979 and January 2005. RESULTS: 17 patients (10 women, 7 men) presenting with parathyroid carcinoma underwent surgical resection. Symptoms were largely related to hypercalcemia. Mean postoperative follow-up was seven years. Local recurrence was noted in four patients (24%) and three patients had late distant metastasis (18%). At the end of the study, nine patients were alive without evidence of recurrence (53%) and one patient was alive with recurrence at 5 years. Seven patients had died, four of whom died as a result of their parathyroid disease. CONCLUSION: Even when symptoms and findings are suggestive, the diagnosis of parathyroid carcinoma is oftentimes difficult. An adequate resection at the first intervention (complete tumor resection including a homolateral thyroid lobectomy and parathyroidectomy with resection of central lymph nodes) is recommended.