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.

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.

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.

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.

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.

Bilateral recurrent laryngeal nerve injury in a specialized thyroid surgery unit: would routine intraoperative neuromonitoring alter outcomes?

BACKGROUND: Bilateral recurrent laryngeal nerve (RLN) palsy following total thyroidectomy is a rare complication, however, poses significant morbidity to the patient when it does occur. The purpose of this paper was to determine the incidence of bilateral RLN palsy in a specialized thyroid unit and determine whether the routine use of intraoperative nerve monitoring (IONM) would alter the outcome. METHODS: This is a retrospective review of prospectively gathered data. A total of 7406 patients underwent total thyroidectomy at the University of Sydney Endocrine Surgical Unit between January 1990 and February 2014. IONM was utilized on a selective basis and we sought to assess whether IONM would have altered outcome in those patients who developed bilateral RLN palsy. RESULTS: Of the 7406 patients who underwent total thyroidectomy, seven patients (0.09%) developed bilateral RLN palsy during the study period. There was one permanent RLN palsy (0.01%) and routine IONM may have prevented one death and altered the outcome in two of the seven patients. CONCLUSION: Bilateral RLN palsy is a rare entity occurring in one out of 1000 cases in a specialized thyroid unit. IONM may facilitate the decision to pursue delayed surgery where the signal is lost on the first surgical side and has the potential to avoid bilateral RLN palsy following total thyroidectomy.

Oxyphil Cell Parathyroid Adenomas Causing Primary Hyperparathyroidism: a Clinico-Pathological Correlation.

Oxyphil cell parathyroid adenomas (OPA) are considered to be an uncommon cause of primary hyperparathyroidism (PHPT), and were historically thought to be clinically silent. It has been our clinical impression that these adenomas present more often than previously thought and may manifest a more severe form of primary hyperparathyroidism than classical adenoma. The aim of this study was to describe the incidence and clinical presentation of OPA. An observational case-control study was undertaken. The study group comprised patients undergoing parathyroidectomy for PHPT where the final pathology confirmed OPA. The controls were made up of an age- and sex-matched group of patients having parathyroidectomy in the same time period where the final pathology confirmed a classical or non-oxyphil adenoma. OPA were defined as parathyroid tumours containing >75% oxyphilic cells. The OPA cases were obtained by reviewing all histopathology slides over an 11-year period (2002-12) where the reports contained the words 'oxyphil' or 'oxyphilic' parathyroid adenomas. These were then reviewed by two independent pathologists to confirm a diagnosis of OPA. The primary outcome measures were preoperative serum calcium and parathyroid hormone (PTH) levels. Secondary outcome measures were symptoms at presentation, accuracy of preoperative localization studies, parathyroid gland weight following surgery, and type of surgery undertaken. In the period 2002-2012, 2739 patients underwent surgery for PHPT. Following pathological review, 91 cases were confirmed as being OPA and formed the study group. A control group (n = 91) from the same period was selected following matching on the basis of age at presentation and sex. OPA were associated with higher preoperative serum calcium (10.84 versus 10.48 mg/dL, p < 0.001) and parathyroid hormone (139 versus 64 ng/L, p < 0.001). At presentation, a lower proportion of OPA cases had asymptomatic disease (15 versus 29%, p = 0.03). There was a trend toward a higher rate of renal calculi at presentation in the OPA group (9 versus 3%, p = 0.07). Preoperative ultrasound was less accurate in localization of OPA when compared with classical adenoma. The rate of minimally invasive surgery was 67% for OPA and 78% for the control group (p = 0.06). All patients were cured of hypercalcaemia at 6-month follow up. There was no significant difference in the weight of removed parathyroid tissue between the groups (868 mg for OPA versus 789 mg for the control group, p = 0.6). OPA are frequently symptomatic and are associated with higher preoperative serum calcium and parathyroid hormone levels than classical types of parathyroid adenomas. OPA are less likely to be localised on preoperative ultrasound examination.

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.

A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma.

Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK-translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease.

Four-dimensional computed tomography for parathyroid localization: a new imaging modality.

INTRODUCTION: Four-dimensional computed tomography (4DCT) is a new parathyroid localization technique not previously reported in Australia. It provides both functional and anatomical imaging in a single test, with superior sensitivity compared with sestamibi scintigraphy (SeS). This study examines the utility of 4DCT in defined clinical situations. METHODS: This is a retrospective cohort study in a tertiary referral hospital setting. One hundred consecutive operative cases of primary hyperparathyroidism (99 patients) undergoing both preoperative 4DCT and SeS. Localization studies were correlated with operative findings, histopathology and clinical outcomes. The utility of 4DCT was analysed in three common clinical settings: primary cases with positive SeS (Group A, n = 68), primary cases with negative SeS (Group B, n = 21) and re-operative cases (Group C, n = 11). RESULTS: The overall sensitivity of 4DCT was 92% compared with 70% for SeS. The sensitivity of 4DCT was superior to SeS in Groups B and C (76% versus 0% and 91% versus 46%, respectively). The overall cure rate was 98%, with 94% of cases completed as minimally invasive procedures. Up to 62% of Group B cases potentially avoided a bilateral neck exploration owing to a positive 4DCT. CONCLUSIONS: 4DCT is an accurate technique providing both functional and anatomical localization of abnormal parathyroid glands. However, the advantage of speed and simplicity in image acquisition needs to be balanced against the small risk of increased radiation exposure in the younger patient group.

Thyroidal abscesses in third and fourth branchial anomalies: not only a paediatric diagnosis.

INTRODUCTION: Acute suppurative thyroiditis and recurrent abscess formation due to third and fourth branchial anomalies typically present in children. However, thyroid abscesses in branchial anomalies may occur in adulthood as well. Failure to recognize and delayed drainage of a neck abscess may lead to a fulminant life-threatening outcome. METHODS: This is a retrospective case series. The study group comprised all patients presenting over a 12-month period from January to December 2012 with thyroid abscesses and a branchial cleft anomaly in two centres, one adult and the other paediatric. Patient demographics, clinical presentation, imaging, surgical management, definitive histology and outcomes were documented. RESULTS: Five patients were identified with a history of thyroid abscesses. Only one was a child (aged 9 years) with the other four being adults (aged 20, 34, 37 and 41 years). All patients had third or fourth left branchial cleft anomalies, presenting as suppurative thyroiditis with a left-sided thyroid abscess. Management options ranged from abscess drainage on initial presentation, primary thyroid lobectomy or delayed thyroid lobectomy following abscess drainage. CONCLUSION: Acute suppurative thyroidits and thyroid abscesses is not just a paediatric diagnosis but may present at any age. In both children and adults, a thyroid abscess almost always arises from branchial cleft anomalies.

Adenomas of cervical maldescended parathyroid glands: pearls and pitfalls.

BACKGROUND: Missed parathyroid adenoma (PTA) is the commonest cause of persistent hyperparathyroidism. Although many are subsequently found in well-described locations, some are found in unusual regions of the neck. This paper presents the combined experience of three large tertiary endocrine surgery centres with maldescended PTA (MD-PTA). METHODS: Patients were recruited from the endocrine surgical databases of three tertiary endocrine surgery units. Patients with PTA found >1 cm above the superior thyroid pole or other cervical locations as a result of abnormal or incomplete descent were included for analysis. RESULTS: MD-PTA was identified in 16 patients out of a total of 5241 patients who had undergone parathyroidectomies in the 7-year study period (incidence 0.3%). Seven (44%) patients had minimally invasive parathyroidectomy, while nine (56%) had bilateral neck exploration. The mean excised gland weight was 750 + 170 mg. Cure was achieved in all patients with a minimum follow-up of 6 months. The locations of MD-PTA in this study included submandibular triangle, retropharyngeal space, carotid sheath (at carotid bifurcation and intravagal), parapharyngeal space (superior to thyroid cartilage or superior thyroid pole) and cricothyroid space. CONCLUSIONS: Despite their rare occurrence, incompletely or abnormally descended PTAs can be encountered by any surgeon who performs parathyroidectomies. It is important to develop a strategy to systematically locate these glands. High cure rates can still be achieved with minimally invasive parathyroidectomy if confident preoperative localization is available. A sound knowledge of embryology and a thorough exploration also facilitate an overall high success rate with open exploration.

Thermal sealing systems with and without tissue divider for total thyroidectomy.

BACKGROUND: Sutureless thyroid surgery utilizing thermal sealing is now well established. However, incremental advances in technology still require formal clinical evaluation in order to ensure that added technology does not compromise safety. In this study, we compared a new thermal sealing device incorporating a tissue divider (LigaSure Small Jaw) with the device we have previously reported for use in total thyroidectomy (LigaSure Precise). METHODS: A cohort study was undertaken of 872 total thyroidectomies over a 2-year period. Patients were selected for each group on the basis of device availability within four institutions and outcomes were obtained from a prospectively maintained database. RESULTS: Small Jaw was used in 399 cases and Precise in 473. No significant differences between patient demographics (sex, age), operation indication or pathology were found. Significantly more Small Jaw operations were performed in private versus public hospitals (P < 0.01). Regarding outcomes, there was no significant difference in the incidence of any complication (haematoma, temporary/permanent hypoparathyroidism or temporary/permanent recurrent laryngeal nerve injury). In a subgroup analysis of operations performed in the public hospital system, Small Jaw was found to be significantly faster (mean operative time: 79 versus 103 min) (95% CI 74-84 and 96-110 min) (P < 0.01). CONCLUSION: The incorporation of a tissue divider into thermal sealing devices is efficacious and safe, with no compromise in clinical outcome, while providing the added benefit of a significant reduction in operative times.

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.

Disease outcomes and nodal recurrence in patients with papillary thyroid cancer and lateral neck nodal metastases.

BACKGROUND: The prognostic influence of lateral neck nodal metastases present at the time of diagnosis of papillary thyroid cancer (PTC) remains controversial. This study aims to document disease outcomes and nodal recurrence rates in such patients. METHODS: Patients with PTC and lateral neck nodal metastases who underwent concurrent total thyroidectomy, central and lateral compartment neck dissection between 2000 and 2010 were identified from the prospectively maintained surgical databases of The University of Sydney and University of Wisconsin Endocrine Surgical Units. Disease outcomes and nodal recurrence rates were compared at 12 months post-operatively and in longer-term follow-up. RESULTS: During this 11-year period, 121 patients were identified. Mean age was 45 years; 58% were female and 98% underwent post-operative radioactive iodine ablation. At a median follow-up of 31 months (range 12-140), there were no disease-specific deaths and disease-free survival (defined by stimulated serum thyroglobulin (Tg) < 2.0 µg/L, negative clinical and radiological examination) was 66%. Of the 50 patients with persistently elevated Tg measured 12 months post-operatively, 15 developed clinical lateral neck nodal recurrence. All have undergone re-operative surgery. Elevated stimulated Tg at 12 months post-operatively and a nodal ratio of >30% were significantly associated with an increased risk of lateral neck nodal recurrence. CONCLUSION: With total thyroidectomy, formal compartmental neck dissection and radioactive iodine treatment, disease-free survival can be achieved in the majority of patients with PTC and synchronous lateral neck nodal metastases. A persistently elevated Tg post-operatively and a high ratio of metastatic nodes identify patients at increased risk of locoregional recurrence.

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.

[Recurrent neck abscess due to a branchial cleft remnant]. / Recidiverend halsabces door een kieuwboogfistel.

BACKGROUND: Abscesses arising from a third or fourth branchial cleft remnant are uncommon clinical entities and are often not recognised in a timely manner. CASE DESCRIPTION: In a 33-year-old female patient with a recurrent abscess in the left side of her neck, the cause turned out to be a fistula in the third branchial cleft remnant. She was treated initially with antibiotics and prednisone without adequate results. When the abscess was finally surgically drained, she became very ill and was admitted to the ICU with sepsis and multiple organ failure. She was discharged from hospital after six weeks. Four months later, a third-branchial cleft remnant was found during pharyngoscopy, immediately after which the cleft remnant fistula was excised and an ipsilateral hemi-thyroidectomy was performed. CONCLUSION: In young patients with recurring peri-thyroidal abscesses, a branchial cleft remnant should be considered a causative factor; this could avoid high morbidity and a delay in the appropriate treatment.

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.