Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.

The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca(2+)i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca(2+)o). Similar pHo effects were observed for Ca(2+)o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca(2+)i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.

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.

Patterns of structural recurrence in papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor-related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. MATERIAL AND METHOD: A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. RESULTS: In the period 1980-2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter, and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P < 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). CONCLUSIONS: In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery.

MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P = .014 and P = .038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P < .01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P = .03 for both). CONCLUSIONS: This study demonstrated that tumor levels of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study.

Level VII is an important component of central neck dissection for papillary thyroid cancer.

BACKGROUND: Therapeutic central neck dissection (CND) is an accepted part of the management of papillary thyroid carcinoma (PTC), while prophylactic CND remains controversial. Regardless of the indication for CND, the lower anatomic border of the central compartment, specifically the inclusion or otherwise of level VII, is not always clearly defined in the literature. This study aimed to determine if the routine inclusion of level VII lymph node dissection as part of CND confers increased utility in the detection of macrometastatic lymph nodes compared with level VI dissection alone. METHOD: This was a prospective cohort study of patients undergoing CND for PTC at a tertiary referral center. All patients received either a prophylactic or therapeutic CND. The CND specimens were divided by the surgeon into level VI and level VII at the level of the suprasternal notch and submitted separately for histopathology. Criteria for macroscopic lymph node disease were taken from the American Joint Committee on Cancer (AJCC) recommendations for breast cancer. RESULTS: A total of 45 patients with PTC underwent total thyroidectomy and routine CND, at a tertiary referral center; 77 % of the therapeutic CND group had positive level VI lymph nodes, and 38 % had positive level VII lymph nodes. Of the prophylactic CND group, 50 % of patients had positive level VI nodes and 16 % has positive level VII nodes detected. All patients with positive level VII lymph nodes in the prophylactic CND group had macrometastatic disease. Temporary hypocalcemia rate was 31 % in the therapeutic group and 6 % in the prophylactic CND group. One patient experienced permanent hypoparathyroidism. There was no vascular injury or recurrent laryngeal nerve palsy in either group. CONCLUSIONS: CND incorporating both level VI and level VII can be undertaken safely through a cervical incision with no increased risk of permanent complications of hypoparathyroidism or recurrent laryngeal nerve injury. Failure to include level VII as part of CND will leave significant macrometastatic nodal disease behind in both therapeutic and prophylactic dissections. As level VII is in direct anatomic continuity with the pretracheal level VI nodes, it should be routinely included as part of every CND.

Is focused minimally invasive parathyroidectomy appropriate for patients with familial primary hyperparathyroidism?

BACKGROUND: The aim of this study was to determine whether a focused minimally invasive parathyroidectomy (MIP) for patients with primary hyperparathyroidism and concordant pre-operative localization studies is appropriate for patients with a family history of the disease. Familial hyperparathyroidism may be seen as a chronic disease in which recurrence is inevitable. Patients frequently undergo subtotal or total parathyroidectomy for perceived 4-gland parathyroid hyperplasia in an attempt to reduce this risk. Controversy remains regarding whether a MIP is appropriate in this setting. METHODS: Patients undergoing an MIP were identified from prospectively maintained databases. Chart review confirmed the presence of a family history of hyperparathyroidism in a direct relative. Patients with and without a family history were compared regarding overall complications, recurrence, and cure rates. RESULTS: A total of 1,652 patients underwent a MIP. Of these, 34 patients had a positive family history. There was no statistically significant difference in age, gender, preoperative biochemistry, gland weight, or complication rates between the groups. The cure rate at 6 months from a single operation was equivalent between the 2 groups (97 vs. 98%). With a median of 39 months follow-up, the recurrence rate was higher in those with a family history compared with those without (8.8 vs 1.1%; P=0.002). Reoperation was successful in the small population of familial patients who did present with recurrent hyperparathyroidism. CONCLUSIONS: The vast majority of patients who underwent a MIP were surgically cured. Although recurrence rates remain higher in the familial hyperparathyroidism group, these data suggest that this alone should not be a contraindication to MIP.

Papillary thyroid carcinoma in pregnancy: a variant of the disease?

BACKGROUND: There are conflicting reports in the literature regarding the prognostic influence of pregnancy on patients with papillary thyroid carcinoma (PTC), and there is no literature on specific microRNA (miRNA) profiles of PTC in the context of pregnancy. We aim to examine clinically if pregnancy is an adverse factor in PTC, and if pregnancy-associated PTC are biologically different from those in nonpregnant women in terms of their miRNA profiles. METHODS: Women diagnosed with PTC during or soon after pregnancy were recruited into the pregnancy group. Age-matched nonpregnant females were recruited into the nonpregnancy group. MiRNA microarray was performed on PTC tissue of pregnant patients (10), nonpregnant patients (10), and normal thyroids (5). There were 6 differentially expressed miRNAs from the microarray comparisons validated with RT-PCR. RESULTS: There were 24 patients in the clinical pregnancy group and 30 in the nonpregnancy group. Tumors from the pregnancy group were significantly larger and showed more regional lymph node metastases. The microarray data showed a total of 27 miRNAs that were potential differentiators of PTC tissue samples from pregnant and nonpregnant patients. Of the 6 selected for validation, no significant difference in expression was found. CONCLUSIONS: Our clinical data suggests that PTC during pregnancy may be more locoregionally aggressive. However, no difference in survival or recurrence is demonstrated. The miRNA profiles of the pregnancy-associated PTC have not been shown to be different to the nonpregnancy counterparts. This likely suggests that the differences seen clinically are related to patient factors rather than the disease itself.

Durability of focused minimally invasive parathyroidectomy in young patients with sporadic primary hyperparathyroidism.

BACKGROUND: Historically, multigland hyperplasia was believed to be the predominant cause of primary hyperparathyroidism (PHPT) in young patients, and hence a relative contraindication for minimally invasive parathyroidectomy. Recent studies, however, demonstrate that the most common aetiology across all age groups is a solitary functioning adenoma. The aim of this study was to compare long-term outcomes in young patients (≤ 45 years), especially those under 30 years of age, with their older counterparts (> 45 years) following focused minimally invasive parathyroidectomy (FMIP). MATERIALS AND METHODS: Patients ≤ 45 years who underwent FMIP between January 1999 and December 2007 were identified from an endocrine surgery database and compared with a matched control group of patients > 45 years old also undergoing FMIP within that time period. The patients' most recent calcium levels (≥ 6 months postoperatively) were examined to establish recurrence rates. Recurrence was defined as an elevation of serum calcium more than 6 months after surgery following initial postsurgical normocalcemia. RESULTS: A total of 117 patients ≤ 45 years and 160 patients > 45 years who underwent FMIP were examined. Follow-up calcium levels were available for 72% of patients. The median length of follow-up was 46 months. No recurrences were identified in both the younger and older cohort of patients; therefore, no statistically significant difference in rates of recurrence could be determined between age groups. CONCLUSION: Recurrence of PHPT following FMIP is rare with no evidence of a higher incidence in younger patients. FMIP can be safely offered to young patients as a long-term durable treatment option.

Parathyroid carcinoma encountered after minimally invasive focused parathyroidectomy may not require further radical surgery.

BACKGROUND: Parathyroid carcinoma accounts for <1% of tumors in primary hyperparathyroidism (PHPT). Distinguishing parathyroid malignancy from benign disease is difficult both before and after initial surgery. Despite the improved specificity of a malignant diagnosis with immunohistochemistry for parafibromin and PGP9.5, proven metastatic behavior remains the gold standard of diagnosis. Minimally invasive focused parathyroidectomy (MIP) is widely performed in patients with PHPT and positive localization studies; thus, it is inevitable that some parathyroid carcinomas will be encountered at MIP. We present our experience of this rare entity. METHODS: The present study represents a surgical case series of patients with parathyroid carcinoma encountered after MIP. The clinicopathological features of benign and malignant parathyroid tumors were compared. Multiple regression analysis was undertaken to compare indicators of malignancy. RESULTS: Between May 1999 and April 2010, a total of 1,292 patients underwent MIP at the University of Sydney Endocrine Surgical Unit, and a histopathological diagnosis of parathyroid carcinoma was made in seven patients (0.5%). Staining for parafibromin and/or PGP9.5 was abnormal in five carcinomas (71%). Despite subsequent unilateral thyroid lobectomy and lymphadenectomy in six patients, no further malignancy was identified in any specimens. Compared to controls, preoperative calcium (p = 0.04) and parathyroid hormone (p = 0.01) were significantly higher in patients with malignancy. The positive predictive value of these parameters for carcinoma was 56 and 75%, respectively. CONCLUSIONS: In patients diagnosed with parathyroid carcinoma after MIP where preoperative imaging had already demonstrated localized disease, revision en bloc surgery did not reveal any residual disease. The benefits of further radical surgery for parathyroid carcinoma after MIP remain controversial.

Parathyroidectomy for patients with secondary hyperparathyroidism in a changing landscape for the management of end-stage renal disease.

BACKGROUND: The landscape of patients with end-stage renal disease is changing with the increasing availability of kidney transplantation. In the near future, a less aggressive approach to treat secondary hyperparathyroidism might be beneficial. We report outcomes of parathyroidectomy for end-stage renal disease-related hyperparathyroidism comparing the outcomes of limited, subtotal, and total parathyroidectomy. METHODS: We performed a retrospective analysis of prospectively collected data. Patients were divided into 3 parathyroidectomy subgroups: limited (<3 glands removed), subtotal (3-3.5 glands), and total (4 glands) parathyroidectomy. Primary outcome was serum levels of parathyroid hormone. Secondary endpoints were serum levels of calcium, phosphate, and alkaline phosphatase, postoperative complications, and persistent or recurrent disease rates. RESULTS: In total, 195 patients were included for analysis of whom 13.8% underwent limited parathyroidectomy, 46.7% subtotal parathyroidectomy, and 39.5% total parathyroidectomy. Preoperative parathyroid hormone levels (pg/mL) were 471 (210-868), 1,087 (627-1,795), and 1,070 (475-1,632) for the limited, subtotal, and total parathyroidectomy groups, respectively (P < .001). A decrease in serum parathyroid hormone was seen in all groups; however, postoperative levels remained greater in the limited parathyroidectomy group compared to the subtotal and total parathyroidectomy groups (P < .001). Serum calcium, phosphate, and alkaline phosphatase levels decreased in all groups to within the reference range. In the limited parathyroidectomy group, persistent disease and recurrence occurred more frequently (P = .02 and P = .07, respectively). CONCLUSION: Subtotal parathyroidectomy is the optimal strategy in an era with an increasing availability of kidney transplantation and improved regimens of dialysis. In this changing practice, the approach to parathyroid surgery, however, might shift to a less aggressive and patient-tailored approach.

The utility of metaiodobenzylguanidine single photon emission computed tomography/computed tomography (MIBG SPECT/CT) for the diagnosis of pheochromocytoma.

BACKGROUND: The enhancement of metaiodobenzylguanidine single photon emission computed tomography (MIBG SPECT) imaging through the addition of CT images fused with SPECT data (coregistered MIBG SPECT/CT imaging) is new technology that allows direct correlation of anatomical and functional information. We hypothesized that MIBG SPECT/CT imaging would provide additional information and improve diagnostic confidence for the radiological localization of a pheochromocytoma, in particular for patients at high risk of multifocal or recurrent disease. METHODS: A retrospective study of all patients investigated by MIBG SPECT/CT at our institution from 2006 to 2008 for a suspected pheochromocytoma was performed. Each case was compared with conventional radiological investigations to determine whether MIBG SPECT/CT was able to improve diagnostic confidence and provide additional diagnostic information compared with conventional imaging alone. RESULTS: Twenty-two patients had MIBG SPECT/CT imaging for a suspected pheochromocytoma. Fourteen patients had positive MIBG SPECT/CT imaging results correlating with imaging by CT or magnetic resonance imaging in all cases. In six cases, MIBG SPECT/CT provided additional information that altered the original radiological diagnosis. Five patients with a pheochromocytoma-associated germline mutation had multifocal disease excluded by MIBG SPECT/CT. Patients without a germline mutation that had positive biochemistry and a solitary lesion with conventional imaging had no diagnostic improvement with MIBG SPECT/CT imaging. CONCLUSIONS: MIBG SPECT/CT fusion imaging is a sensitive and specific radiological imaging tool for patients suspected to have pheochromocytoma. The particular strengths of MIBG SPECT/CT are detection of local recurrence, small extra-adrenal pheochromocytomas, multifocal tumors, or the presence of metastatic disease.

Hyperparathyroidism in pregnancy: options for localization and surgical therapy.

BACKGROUND: Hyperparathyroidism in pregnancy is a threat to the health of both mother and fetus. The mothers suffer commonly from nephrolithiasis, hyperemesis, or even hypercalcemic crisis. Untreated disease will commonly complicate fetal development and fetal death is a significant risk. Treatment options, including medical and surgical therapy, are debated in the literature. METHODS: This is a case series comprising seven patients with primary hyperparathyroidism in pregnancy. Data collected included symptoms at diagnosis, biochemical abnormalities, pathologic findings, treatment regimes, and subsequent maternal and fetal outcomes. RESULTS: Seven women, aged 20 to 39 years, presented with hyperparathyroidism during pregnancy. The earliest presented at 8 weeks and the latest at 38 weeks. Four of seven patients experienced renal calculi. Calcium levels were 2.7-3.5 mmol/l. All were found to have solitary parathyroid adenomas, of which two were in ectopic locations. Fetal complications included three preterm deliveries and one fetal death with no cases of neonatal tetany. Maternal and fetal complications could not be predicted based on duration or severity of hypercalcemia. Three patients were treated during pregnancy with surgery, and two of these had ectopic glands that required reoperations with a novel approach using Tc-99m sestamibi scanning during pregnancy to assist in localizing the abnormal gland. Four cases were treated postpartum with a combination of open and minimally invasive approaches after localization. No operative complications or fetal loss related to surgery were observed in this cohort. CONCLUSIONS: Primary hyperparathyroidism in pregnancy represents a significant risk for maternal and fetal complications that cannot be predicted by duration of symptoms or serum calcium levels. Surgical treatment should be considered early, and a minimally invasive approach with ultrasound is best suited to mitigating risk to mother and fetus. Equally important, Tc-99m sestamibi imaging may be used safely for localization of the parathyroids after negative cervical explorations.

Diagnostic utility of fine-needle aspiration cytology in pediatric differentiated thyroid cancer.

BACKGROUND: Pediatric patients present with thyroid nodules less often than adults, but the rate of malignancy is much higher. This study was designed to determine the ability of fine-needle aspiration cytology (FNA) to diagnose accurately and facilitate management of thyroid neoplasms in pediatric patients. METHODS: A retrospective study revealed 110 patients <19 years old who had undergone thyroid surgery and FNA biopsy at two academic institutions over the last 28 years. FNA sensitivity for diagnosing papillary thyroid cancer (PC) and follicular neoplasm (FN) was investigated. RESULTS: Of 110 patients who presented for surgery, 27 had PC and 33 had a FN: 4 follicular carcinomas (FCs) and 29 follicular adenomas (FAs). Among the PCs patients, the FNA results were as follows: 1 (4%) nondiagnostic, 6 (22%) atypical, 2 (7%) benign, and 18 (67%) malignant lesions. The sensitivity of a malignant FNA was 90% for diagnosing a PC. Sensitivity of an atypical FNA was 75% for FCs and 69% for FAs, giving an overall FN sensitivity of 70%. Of the atypical FNA readings, 60% had confirmed histological atypical features, and 19% were malignant. In 95% of the malignant FNA reports, final histology confirmed PC, resulting in a positive predictive value of 95%. CONCLUSIONS: FNA biopsy can reliably diagnose malignancy in pediatric thyroid patients and should be used as a standard technique to indicate surgical treatment. Atypical or suspicious FNA results do not predict cancer effectively, confirming the current accepted practice for adults that diagnostic excision is required to exclude malignancy in pediatric patients.

Surgery alone for papillary thyroid microcarcinoma is less costly and more effective than long term active surveillance.

BACKGROUND: Papillary thyroid microcarcinoma is a subtype of thyroid cancer that may be managed with active surveillance rather than immediate surgery. Active surveillance decreases complication rates and may decrease health care costs. This study aims to analyze complication rates of thyroid surgery, papillary thyroid microcarcinoma recurrence, and survival rates. Additionally, the costs of surgery versus hypothetic active surveillance for papillary thyroid microcarcinoma are compared in an Australian cohort. METHODS: Papillary thyroid microcarcinoma patients were included from a prospectively collected surgical cohort of patients treated for papillary thyroid cancer between 1985 and 2017. The primary outcomes were the complications of thyroid surgery, recurrence-free survival, overall survival, and cost of surgical treatment and active surveillance. RESULTS: In a total of 349 patients with papillary microcarcinoma with a median age of 48 years (range, 18-90 years), the permanent operative complications rate was 3.7%. Postoperative radioactive iodine did not decrease recurrence-free survival (P = .3). The total cost of surgical treatment was $10,226 Australian dollars, whereas hypothetic active surveillance was at a yearly cost of $756 Australian dollars. Estimated cost of surgical papillary thyroid microcarcinoma treatment was equivalent to the cost of 16.2 years of active surveillance. CONCLUSION: Surgery may have a long-term economic advantage for younger Australian patients with papillary thyroid microcarcinoma who are likely to require more than 16.2 years of follow-up in an active surveillance scheme.

A Proposed Grading Scheme for Medullary Thyroid Carcinoma Based on Proliferative Activity (Ki-67 and Mitotic Count) and Coagulative Necrosis.

We investigated the prognostic value of a range of histologic parameters in medullary thyroid carcinoma (MTC) to design a grading system to predict overall survival. We assessed 76 patients with MTCs undergoing primary tumor resection for age, sex, tumor size, vascular space invasion, lymph node metastasis, multiple endocrine neoplasia type 2 (MEN2) status, mitotic count, Ki-67 proliferative index, spindled morphology, sheet-like growth pattern, coagulative necrosis, incipient necrosis, nuclear grade, multinucleation, prominent nucleoli, fibrosis, and amyloid deposition. In addition to the clinical features of age and the diagnosis of MEN2, the only histologic features that significantly predicted reduced overall survival were Ki-67 proliferative index, mitotic count, and the presence of coagulative necrosis. Using a combination of these 3 variables, we propose a 3-tiered grading system based solely on proliferative activity (Ki-67 proliferative index and mitotic count) and necrosis. There were 62 (82%) low-grade MTCs (low proliferative activity, no necrosis), 9 (12%) intermediate grade (low proliferative activity and necrosis present, or intermediate proliferative activity and no necrosis), and 5 (7%) high grade (intermediate proliferative activity and necrosis present, or high proliferative activity with or without necrosis). The mean overall survival was 193, 146, and 45 months, respectively (P=0.0001) for the 3 grades. The grading system remained prognostic when controlled for other factors associated with survival including age and known MEN2 syndrome. We conclude that this proposed grading system, which uses only a combination of proliferative activity (Ki-67 index, mitotic count) and coagulative necrosis, is a strong predictor of overall survival in MTC.

Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma.

CONTEXT: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed. OBJECTIVE: We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma. DESIGN: In total, 146 parathyroid tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-jaw tumor syndrome-related tumors and 24 sporadic carcinomas. RESULTS: In tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for the detection of parathyroid carcinoma and/or HRPT2 mutation and a specificity of 100%. Complete lack of nuclear parafibromin staining had a sensitivity of 67% and a specificity of 100%. PGP9.5 was positive in a tumor with the HRPT2 mutation L64P that expressed parafibromin. Furthermore, UCHL1 was highly expressed in the carcinoma/hyperparathyroidism-jaw tumor syndrome group compared to normal (P < 0.05) and benign specimens (P < 0.001). CONCLUSION: These results suggest that positive staining for PGP9.5 has utility as a marker for parathyroid malignancy, with a slightly superior sensitivity (P = 0.03) and similar high specificity to that of parafibromin.

Outcomes of surgically managed pediatric thyroid cancer.

BACKGROUND: Thyroid cancer is the most common carcinoma in children, and compared with adults, generally present with more advanced disease. Management is similar between populations, primarily consisting of total thyroidectomy. With similar treatment despite disease severity, we chose to explore the surgical outcome of pediatric patients with thyroid malignancy. METHODS: A review of medical records at two academic institutions revealed 68 patients<19 y of age who underwent surgical resection of a malignant thyroid nodule between 1962 and 2008. RESULTS: Of 68 pediatric surgery patients identified with thyroid malignancy, 50 patients (74%) had a total thyroidectomy. Minor complications were noted in 21% of surgeries with 19% temporary hypocalcemia. Risk of complication was not associated with type of surgery. Patients receiving a lobectomy or subtotal thyroidectomy were at greater risk for needing a second surgical procedure, required by 14 patients (21%). CONCLUSIONS: There was no significant increase in surgical complications with respect to type of surgery, however, patients receiving less than total thyroidectomy were at increased risk of repeat surgery. Total thyroidectomy is recommended as the standard of care for the management of pediatric thyroid cancer.

Treatment strategy of end stage renal disease-related hyperparathyroidism before, during, and after the era of calcimimetics.

BACKGROUND: Since 2004, end-stage renal disease related hyperparathyroidism patients are treated mainly with cinacalcet, which ceased to be subsidized through the Australian Pharmaceutical Benefits Scheme in 2015. We aimed to investigate the impact of these changes on the treatment strategy in the Australian end-stage renal disease population. METHODS: The following groups were formed according to the date of parathyroidectomy: A, before calcimimetics; B, during the era of calcimimetics; and C, after cinacalcet removal by the Australian Pharmaceutical Benefits Scheme. The primary outcome was time from start of dialysis to parathyroidectomy. Regression analysis was used to examine trends in parathyroidectomy rates. RESULTS: Between 1998 and 2016, 195 parathyroidectomies were performed. Median time to referral was 69 (33-123), 67 (31-110) and 44 (23-102) months for groups A, B, and C, respectively (P = .55). Parathyroidectomy rates increased throughout the years (CI 0.09-1.13, R2=0.27, P = .02). A trend toward a dip in parathyroidectomy rates was seen during the era of cinacalcet (P = .08). Median preoperative parathyroid hormone levels increased significantly (842 [418-1,553] versus 1,040 [564-1,810] versus 1,350 [1,037-1,923] pg/mL, for groups A, B, and C, respectively [P < .01]). CONCLUSION: Parathyroidectomy rates seem to vary according to the availability of cinacalcet. This change in treatment strategy is accompanied with increased preoperative parathyroid hormone levels, reflecting delayed surgery and increased disease severity.

Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features.

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.

Heterogeneous expression of SNARE proteins SNAP-23, SNAP-25, Syntaxin1 and VAMP in human parathyroid tissue.

In regulated exocytosis synaptosomal-associated protein of 25kDa (SNAP-25) is one of the key-players in the formation of SNARE (soluble N-ethylmaleimide-sensitive fusion attachment protein receptor) complex and membrane fusion. SNARE proteins are essentially expressed in neurons, neuroendocrine and endocrine cells. Whether parathyroid cells express these proteins is not known. In this study, we have examined the expression of the SNARE protein SNAP-25 and its cellular homologue SNAP-23, as well as syntaxin1 and VAMP (vesicle-associated membrane protein) in samples of normal parathyroid tissue, chief cell adenoma, and parathyroid carcinoma, using immunohistochemistry and Western blot analysis. SNAP-23 and VAMP were evenly expressed in all studied parathyroid tissues using immunohistochemistry and/or Western blot analysis. SNAP-25 (and Syntaxin1) was not expressed in normal parathyroid tissue, but in approximately 20% of chief cell adenomas, and in approximately 45% of parathyroid carcinoma samples. It is likely that the SNARE proteins SNAP-23 and VAMP play a role in the stimulus-secretion coupling and exocytosis of parathyroid hormone as these proteins were expressed in all of the parathyroid samples we studied. In particular, preferential expression of SNAP-23 rather than SNAP-25 provides an explanation of the high level of PTH secretion that occurs under conditions of low cytoplasmic free Ca(2+) concentration (around 0.1micromol/l). SNAP-25 (and Syntaxin1) appears to be a tumour-specific protein(s) in parathyroid tissues since its expression was restricted to pathological tissues.