Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma- SIZEPASS.

Aim: We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL). Methods: This single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy. Results: 76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p<0.0001). Across PPGL, SIZEPASS >1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P<0.001). It retained an accuracy >90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status. Conclusions: The SIZEPASS>1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status.

Defining the feasibility of same day adrenalectomy - A prospective matched cohort study.

Background: Despite technical advances, day surgery still accounts for <1 % of adrenal procedures. We investigated feasibility and safety of same day adrenalectomy (SDA). Methods: Between We recruited 30 patients with primary hyperaldosteronism (PHA) or Cushing's syndrome (CS) into a prospective matched, single centre cohort study to evaluate the impact of exposure to a same day discharge pathway (SDA cohort; n = 10) or inpatient adrenalectomy (PIPA cohort; n = 20). We compared results to a matched cohort (n = 40) from our prospective in-patient adrenalectomy registry (RIPA cohort). Results: Mean age was 51.3 ± 8.5 years, with 43 % female, 3.3 % ASA I and 96.7 % ASA II. Lesion size was 17 ± 9 mm (range 5-40 mm). 80 % of patients presented with PHA. The predefined primary endpoint (discharge on same calendar day without major complications, emergency presentation or readmission) was achieved in 100 % of SDA, but none of the in-patients (χ2 = 57; p < 0.0001). The secondary endpoint (discharge within 23 h of surgery without major complications, emergency presentation or readmission) was achieved in 100 % of SDA, 90 % of PIPA (n.s.), 33 % of RIPA (33 %; χ2 = 14.6 p < 0.001), and 51.5 % of IPA patients (χ2 = 8.5 p < 0.01). Combining SDA and PIPA cohorts, 93.3 % of treatment episodes met widely used (WHO, United States) definitions of day surgery as completion of the hospital care episode within 23 h. Patients admitted for SDA were highly satisfied (100 %). Conclusion: Same day discharge after adrenalectomy is feasible, safe, and well-perceived in appropriately selected patients with PHA and Cushing's syndrome.

Mediastinal Parathyroid Cancer.

Parathyroid cancer (PC) is rare, but its pre-operative recognition is important to choose appropriate access strategies and achieve oncological clearance. This study characterizes features of mediastinal parathyroid cancer (MPC) and explores criteria aiding in the pre-operative recognition of malignancy. We assembled data from 502 patients with mediastinal parathyroid neoplasms (MPNs) from a systematic review of the literature 1968−2020 (n = 467) and our own patient cohort (n = 35). Thirty-two of the 502 MPNs (6.4%) exhibited malignancy. Only 23% of MPC patients underwent oncological surgery. Local persistence and early recurrence at a median delay of 24 months were frequent (45.8%), and associated with a 21.7-fold (95%CI 1.3−351.4; p = 0.03) higher risk of death due to disease. MPCs (n = 30) were significantly larger than cervical PC (n = 330), at 54 ± 36 mm vs. 35 ± 18 mm (χ2 = 20; p < 0.0001), and larger than mediastinal parathyroid adenomas (MPA; n = 226) at 22 ± 15 mm (χ2 = 33; p < 0.01). MPC occurred more commonly in males (60%; p < 0.01), with higher calcium (p < 0.01) and parathyroid hormone (PTH) levels (p < 0.01) than MPA. Mediastinal lesions larger than 3.0 cm and associated with a corrected calcium ≥ 3.0 mM are associated with a more than 100-fold higher odds ratio of being malignant (OR 109.2; 95%CI 1.1−346; p < 0.05). The composite 3 + 3 criterion recognized 74% of all MPC with an accuracy of 83%. Inversely, no MPN presenting with a calcium < 3.0 mM and size < 3.0 cm was malignant. When faced with pHPT in mediastinal location, consideration of the 3 + 3 rule may trigger an oncological team approach based on simple, available criteria.

Margin Free Resection Achieves Excellent Long Term Outcomes in Parathyroid Cancer.

Long-term outcomes of parathyroid cancer remain poorly documented and unsatisfactory. This cohort includes 25 consecutive parathyroid cancer patients with median follow-up of 10.7 years (range 4.1−26.5 years). Pre-operative work-up in the center identified a suspicion of parathyroid cancer in 17 patients. En bloc resection, including the recurrent laryngeal nerve in 4/17 (23.5%), achieved cancer-free resection margins (R0) in 82.4% and lasting loco-regional disease control in 94.1%. Including patients referred after initial surgery elsewhere, R0 resection was achieved in merely 17/25 (68.0%) of patients. Cancer-positive margins (R1) in 8 patients led to local recurrence in 50%. On multivariate analysis, only margin status prevailed as independent predictor of recurrence free survival (χ2 19.5, p < 0.001). Local excision alone carried a 3.5-fold higher risk of positive margins than en bloc resection (CI95: 1.1−11.3; p = 0.03), and a 6.4-fold higher risk of locoregional recurrence (CI95: 0.8−52.1; p = 0.08). R1-status was associated with an 18.0-fold higher risk of recurrence and redo surgery (CI95: 1.1−299.0; p = 0.04), and a 22.0-fold higher probability of radiation (CI95: 1.4−355.5; p = 0.03). In patients at risk, adjuvant radiation reduced the actuarial risk of locoregional recurrence (p = 0.05). When pre-operative scrutiny resulted in upfront oncological surgery achieving cancer free margins, it afforded 100% recurrence free survival at 5- and 10-year follow-up, whilst failure to achieve clear margins caused significant burden by outpatient admissions (176 vs. 4 days; χ2 980, p < 0.001) and exposure to causes for concern (1369 vs. 0 days; χ2 11.3, p = 0.003). Although limited by cohort size, our study emphasizes the paradigm of getting it right the first time as key to improve survivorship in a cancer with excellent long-term prognosis.

Long-term quality of voice is usually acceptable after initial hoarseness caused by a thyroidectomy or a parathyroidectomy.

BACKGROUND: Vocal cord (VC) palsy following a thyroidectomy or parathyroidectomy can result in significant morbidity for the patient. We aimed to investigate the incidence of VC palsy in a tertiary referral Institution, track the management of these cases and record the long-term outcomes and VC recovery rates. METHODS: Retrospective review of all thyroidectomy/parathyroidectomy operations performed over 11 years. Patients with an unequivocal hoarse voice postoperatively were included. We analysed the patient's clinical characteristics and voice outcomes, operative, pathology and laryngoscopy reports during their follow-up. RESULTS: Ten patients fitted the inclusion criteria and were analysed. Median age at date of operation was 47.5 years (range, 16-81 years) and the M:F ratio was 1:2.3 (M:3, F:7). The median FU was 62.5 months (range, 12-144 months). The median hospital stay was 1.5 days (range, 1-87 days). There were 7 recurrent laryngeal nerve (RLN) injuries by manipulation, 1 case of RLN resection, 1 inadvertent division (with primary nerve repair) and 1 RLN was shaved off the thyroid. Long-term voice outcomes for the 7 patients with an RLN manipulation injury were: 3/7 patients had normal voice, 3/7 had moderate hoarseness and 1/7 had long-term hoarseness. The long-term voice outcome of the patient with RLN shaving off the thyroid gland was excellent while the 2 remaining patients (RLN resection and inadvertent division) needed 12 and 18 months respectively to achieve a normal quality of voice. Four out of the 10 patients had permanent VC palsy in the long-term and their voice outcomes varied: 1 patient had a normal voice, 2 patients had moderate hoarseness and 1 patient had persistent hoarseness. Only 1/10 patients did not show any voice improvement after 12 months. CONCLUSIONS: In the vast majority of cases post-operative hoarseness due to RLN palsy improves in the long-term, albeit voice may not return completely to normal.

18F-FDG PET rarely provides additional information to 11C-methionine PET imaging in hyperparathyroidism.

AIM: The aim of this study was to assess the utility of combined C-methionine and F-FDG PET/CT imaging in hyperparathyroidism. PATIENTS AND METHODS: We reviewed all scans performed for hyperparathyroidism with both C-methionine and F-FDG PET/CT or PET in our institution since 1993. Forty-three patients (47 pairs of scans) were included (13 men and 30 women) with a mean age of 63 years. C-methionine and F-FDG PET/CT scans were classified as positive or negative for localization of abnormal parathyroid tissue, and the site of uptake was noted in the positive scans. Other concurrent imaging (Tc-MIBI scintigraphy, ultrasonography, CT, or MRI) findings were also noted when performed. Clinical follow-up information was available in 27 patients (30 episodes). RESULTS: Of the 47 PET scan episodes, 23 (49%) were positive. Twenty-two C-methionine scans showed abnormal focal localization of which 10 also showed concordant abnormal F-FDG uptake. One patient was positive with F-FDG and negative with C-methionine.Of the 16 patients who underwent subsequent surgery, 6 had concordant C-methionine, F-FDG, and surgical findings; 6 had concordant C-methionine and surgical findings; 1 had concordant F-FDG and surgical findings; and 3 had both PET scans negative but had adenomas excised during surgery.Of the 3 with both PET scans negative and discordant surgical findings, 1 had mediastinal parathyroid lipoadenoma excised and 2 had normally sited parathyroid adenoma excised. CONCLUSIONS: F-FDG PET/CT rarely provides additional information and could be saved for patients in whom C-methionine PET/CT is negative.

Diagnosis and management of parathyroid cancer.

Parathyroid cancer is rare, but often fatal, as preoperative identification of malignancy against the backdrop of benign parathyroid disease is challenging. Advanced genetic, laboratory and imaging techniques can help to identify parathyroid cancer. In patients with clinically suspected parathyroid cancer, malignancy of any individual lesion is established by three criteria: demonstration of metastasis, specific ultrasonographic features, and a ratio >1 for the results of third-generation:second-generation parathyroid hormone assays. Positive findings for all three criteria dictate an oncological surgical approach, as appropriate radical surgery can achieve a cure. Mutation screening pinpoints associated conditions and asymptomatic carriers. Molecular profiling of tumour cells can identify high-risk features, such as differential expression of specific micro-RNAs and proteins, and germ line mutations in CDC73, but is unsuitable for preoperative assessment owing to the potential risks associated with biopsy. A validated, histopathology-based prognostic classification can identify patients in need of close follow-up and adjuvant therapy, and should prove valuable to stratify clinical trial cohorts: low-risk patients rarely die from parathyroid cancer, even on long-term follow-up, whereas 5-year mortality in high-risk patients is around 50%. This insight has improved the approach to parathyroid cancer by enabling risk-adapted surgery and follow-up.

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.

Surgery in Castleman's disease: a systematic review of 404 published cases.

OBJECTIVES: We undertook a systematic review of 404 published cases of Castleman's disease to identify the role of the surgeon beyond assistance in tissue-based diagnosis. BACKGROUND: Castleman's disease is a rare primary disease of the lymph node caused by infection with herpesviridae. Little is known about the role of surgery in this condition. DATA SOURCES: Medline, Embase, Cochrane Database of Systematic Reviews, ISI Thompson Web of Knowledge, and hand search of articles' bibliography. STUDY SELECTION: Of the 1791 citations identified through the initial electronic search and screened for possible inclusion, 488 articles were retained after title and abstract reviews. Of these, 239 were accepted for this review. DATA EXTRACTION: A complete dataset containing age, gender, centricity (unicentric vs multicentric), histopathologic type (hyaline vascular [HV] vs plasma cell [PC]), anatomical location of the only focus in unicentric Castleman's disease (UCD) or the dominant focus in multicentric Castleman's disease (MCD), nature of the surgical approach (resective vs diagnostic), and outcome (disease-free survival [DFS] vs death due to disease) was extracted. RESULTS: A resective or debulking surgical approach was described in 77.0% of all patients, but was far more common in unicentric (262/278; 94.2%) than multicentric (49/126; 38.9%) disease (χ² 146.8; P < 0.0001). Unicentric disease had a significantly higher overall survival (95.3% vs 61.1%; χ² 55.7; P < 0.0001), 3 year DFS (89.7% vs 55.6%; χ² 27.8; P < 0.0001), and 5 year DFS (81.2% vs 34.4%; χ² 28.6; P < 0.0001) than multicentric disease. Failure to treat unicentric disease by resective surgery resulted in a significant mortality (17.6% vs 3.8% χ²; P < 0.05). In multicentric disease, outcomes are comparable between debulking surgery alone, immunochemotherapy alone, or a combination of both (28.0% vs 28.9% vs 50.0%; P = nonsignificant). CONCLUSIONS: Surgery is the gold standard for treatment of unicentric Castelman's disease. The role of debulking surgery in human immunodeficiency virus (-) MCD needs to be evaluated in prospective studies.

Inflammatory diseases of the parathyroid gland.

AIMS: Inflammatory disorders of the parathyroid gland are very rare as compared with those of other endocrine organs. The aim of this study was to provide the first systematic review of this condition. METHODS AND RESULTS: A 42-year-old patient underwent surgery for recurrent secondary hyperparathyroidism. Histology showed hyperplastic parathyroiditis defined by a mixed inflammatory infiltrate with active germinal centres. Molecular markers revealed significant upregulation of CD68 in an ischaemic background (hypoxia-inducible factor 1 upregulation) with mitochondrial reaction (malate dehydrogenase 2 upregulation) and hyperparathyroidism (carbonic anhydrase 4 upregulation). Our case demonstrates true intraparathyroid inflammation with terminal B-cell differentiation. We searched PubMed, ISI Thompson and Google Scholar up to January 2011, using the terms 'parathyroiditis', 'inflammation of parathyroid gland', 'lymphocytic infiltrate', 'tuberculosis of the parathyroid', 'sarcoidosis', and 'graulomatous inflammation'. Three autopsy series, 27 articles and 96 case reports with inflammatory parathyroid disorders were identified. Autopsy series showed lymphocytic infiltrates in up to 16% of all cases. The entire material reported lymphocytic infiltrates (n=69), parathyroiditis with germinal centres (n=15), sarcoidosis (n=6), tuberculosis (n=4), and other granulomatous diseases (n=2). CONCLUSIONS: Distinct inflammatory and granulomatous processes in the parathyroid gland are rare. Scanty lymphocytic infiltrates are common, and occur in generalized inflammatory conditions or venous congestion. We note the surprising absence of an association between histological proof of parathyroiditis and hypoparathyroidism.

Castleman's disease: systematic analysis of 416 patients from the literature.

BACKGROUND: Castleman's disease is a rare primary disease of the lymph nodes with limited available clinical information. METHODS: A systematic literature search identified 416 cases amenable to detailed analysis. RESULTS: In HIV(-) patients, centricity, pathology type, the presence of symptoms, gender, and age all predict outcome in univariate analyses. The 3-year disease-free survival (DFS) rate for patients with unicentric hyaline vascular disease (49.5% of cases, class I) was 92.5%, versus 45.7% for those with multicentric plasma cell disease (20.2% of cases, class III) and 78.0% for those with any other combination (22.6% of cases, class II) (p < .0001). HIV(+) patients (class IV) exclusively presented with multicentric plasma cell disease and had a 3-year DFS rate of only 27.8%. Kaposi's sarcoma and lymphoma were observed in 59.3% and 9.4% of HIV(+) patients and in 2.6% and 3.6% of HIV(-) patients (p < .0001). Paraneoplastic pemphigus and the syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes were observed exclusively in HIV(-) patients at a rate of 1.3% and 1.8%, respectively. CONCLUSION: Clinical, pathological, and viral markers allow for the classification of Castleman's disease into groups with markedly different outcomes and disease associations.

Ultrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm.

OBJECTIVE: Nearly all reported parathyroid cancers are >15 mm at presentation. The objective was to identify ultrasound criteria of malignancy in parathyroid lesions of >15 mm in size. MATERIALS AND METHODS: This study was approved by a local ethics committee. A retrospective review of patients identified from a database from 2004-2009 was performed. All patients underwent ultrasound imaging according to the protocol. Two trained observers categorized findings using the pre-determined features: shape, calcification, pattern of vascularity, local infiltration and internal lesion gray scale appearances. RESULTS: Sixty-nine patients (mean age 54.3 years, range 19-79 years; male = 16, female = 53) fulfilled the criteria of a parathyroid lesion >15 mm; 8/69 (11.6%) with parathyroid cancer and 61/69 (88.4%) with benign solitary parathyroid adenoma. A high positive predictive value (PPV) for cancer was identified for infiltration (PPV 100%) and calcification (PPV 100%), whilst a high negative predictive value (NPV) was found for the absence of suspicious vascularity (NPV 97.6%), a thick capsule (NPV 96.7) and inhomogeneity (NPV 100%). CONCLUSION: In lesions >15 mm systematic ultrasound assessment of specific features provides a valuable tool to identify parathyroid cancers before surgery.

Retroperitoneal unicentric Castleman's disease with multiple lymph node involvement.

A 78-year-old woman with B-symptoms was referred for a left adrenal incidentaloma of 5 cm. Imaging revealed features compatible with adrenal cancer. The authors excluded excess production of catecholamines or adrenal steroids. The tumour was removed by en bloc radical left retroperitonectomy with adrenalectomy, nephrectomy, interaortocaval lymphadenectomy and splenectomy. Histology demonstrated periadrenal hyaline vascular Castleman's disease with local infiltration and 14 positive lymph nodes. The lymphoid infiltrate spilled into the adjacent renal cortex. HHV8 was negative. The Ki67 proliferative index was 30-40% in germinal centres. There was no syn- or metachronous disease on extended imaging including fluorodeoxyglucose positron emission tomography-CT and narrow follow-up at 3 years. This is a rare case of unicentric hyaline vascular Castleman's disease with documented locoregional lymph node involvement. The case exemplifies the transition from unifocal unicentric disease into disseminated disease with involvement of multiple lymph node stations (multicentric disease). The authors demonstrate surgical cure by oncological resection.

Lymph node involvement and surgical approach in parathyroid cancer.

BACKGROUND: The best surgical approach to parathyroid cancer is disputed. Recommendations vary and are built on incoherent evidence. High rates of recurrence and death require an in-depth review of underlying findings. METHODS: This retrospective study includes 11 patients with parathyroid cancer who underwent surgery with central and/or lateral neck dissection by a single surgeon between 2005 and 2010. The diagnosis was based on histopathological criteria in all patients. Patterns of lymph node and soft tissue involvement of these and formerly reported patients were analysed based on full-text review of all published cases of parathyroid cancer. RESULTS: In this series only 1 of 11 patients (9.1%) manifested lymph node metastasis. In the literature, lymph node metastases have been reported in only 6.5% of 972 published patients, or in 32.1% of the 196 in whom lymph node involvement was assessed by the authors. They were, with few exceptions, localised in the central compartment. Recurrence in soft tissue is more frequent than in locoregional lymph nodes. CONCLUSION: Oncological en bloc clearance of the central compartment with meticulous removal of all possibly involved soft tissues, including a systematic central lymph node resection, may improve outcomes and should be included in the routine approach to the suspicious parathyroid lesion. There is no need for a prophylactic lateral neck dissection.

Castleman's disease--a two compartment model of HHV8 infection.

Castleman's disease is a primary infectious disease of the lymph node that causes local symptoms or a systemic inflammatory syndrome. Histopathology reveals a destroyed lymph node architecture that can range from hyaline-vascular disease to plasma-cell disease. Viral interleukin 6 (vIL-6) produced during the replication of human herpesvirus type 8 (HHV8) is the key driver of systemic inflammation and cellular proliferation. Stage progression of Castleman's disease results from switches between viral latency and lytic replication, and lymphatic and hematogenous spread. Multicentric plasma-cell disease in HIV-1 patients is associated with HHV8 infection. Polyclonal plasmablast proliferation escapes control in the germinal center with eventual malignant transformation into non-Hodgkin lymphoma. Surgery produces excellent results in unicentric disease, while multicentric disease responds to anti-CD20 therapy or IL-6 and chemotherapy. Lymphovascular endothelium and naive B cells are infectious reservoir-opening options for antiangiogenic and anti-CD19 strategies to enhance outcomes in patients with systemic disease.

The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A.

BACKGROUND: Germline missense mutations of the RET protooncogene cause a clinical spectrum called multiple endocrine neoplasia (MEN) type 2. A strong genotype-phenotype correlation results in major implications for the clinical approach. More information on less common mutations is needed to advance specific guidance. PATIENTS AND METHODS: We report individualized patient information on 36 carriers of the intracellular RET gene mutation S891A from three centers and clustered data of 38 former patients reported in the literature in nine additional studies. RESULTS: S891A mutation accounts for up to 5% of all patients to date reported with RET mutations and 16% of those hitherto reported with intracellular mutations. S891A mutation caused medullary thyroid cancer (MTC) in 69.4%, pheochromocytoma in 2.8%, and parathyroid hyperplasia in 8.3% of the 36 patients of this case series and in 63.5, 4.1, and 4.1%, respectively, for the entire groups of 74 patients. The youngest age of onset for MTC in this group was 17 yr (median, 46 yr; range, 17-80 yr), for pheochromocytoma 46 yr (median, 46 yr), and for parathyroid hyperplasia 17 yr (median, 20 yr, range, 17-46 yr). Persistence of MTC was described in 14.3% of patients with available follow-up. Additional findings included corneal nerve thickening in three of 74 patients (4.1%). CONCLUSION: This intracellular mutation can initiate the full spectrum of MEN2a, initiates MTC at an early age, and causes recurrence and death if undertreated. We recommend stringent adherence to established guidance in MEN2a in this rare mutation.

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.