Clinical Significance of Pheochromocytoma Size on the Timing and Extent of Surgery.

INTRODUCTION: Elevated metanephrine and catecholamine levels 3-fold upper limit of normal (ULN) are diagnostic for pheochromocytoma. We sought to determine whether size correlates with biochemical activity or symptoms which could guide timing of surgery. METHODS: Data from consecutive patients undergoing adrenalectomy for pheochromocytoma at our institution over a 10-year period were retrospectively collected. These included maximal lesion diameter on preoperative imaging, plasma/urine metanephrine and/or catecholamine levels, demographic variables and presence of typical paroxysmal symptoms. Receiver operating characteristic curves were used to assess predictive accuracy. RESULTS: Sixty-three patients were included in the analysis (41 females and 22 males). Median age was 56 (43, 69) years. Due to various referring practices, 31 patients had documented 24-h urine metanephrine, 26 had 24-h urine catecholamine, and 52 had fractionated plasma metanephrine levels available for review. Values were converted to fold change compared to ULN and the maximum of all measured values was used for logistic regression. Median tumor size was 3.40 (2.25, 4.55) cm in greatest dimension. Tumor size at which pheochromocytoma produced > 3-fold ULN was ≥2.3 cm (AUC of 0.84). Biochemical activity increased with doubling tumor size (odds ratio = 8, P = 0.0004) or ≥ 1 cm increase in tumor size (odds ratio = 3.03, P = 0.001). 40 patients had paroxysmal symptoms, but there was no significant correlation between tumor size/biochemical activity and symptoms. CONCLUSIONS: In our study, tumor size directly correlated with the degree of biochemical activity and pheochromocytomas ≥2.3 cm produced levels 3 times ULN. These findings may allow clinicians to adjust timing of operative intervention.

Total Thyroidectomy vs Thyroid Lobectomy for Localized Papillary Thyroid Cancer in Children: A Propensity-Matched Survival Analysis.

BACKGROUND: Current guidelines recommend total thyroidectomy (TT) and radioablation for most papillary thyroid cancer (PTC) in children. These guidelines have been criticized as aggressive, especially for early-stage PTC, as it likely does not influence patient survival and results in life-long thyroid hormone replacement. We sought to study whether the extent of thyroidectomy (TT vs thyroid lobectomy [TL]) influences overall and disease-specific survival in children with localized PTC. METHODS: The National Cancer Database and the Surveillance, Epidemiology, and End Results registries were queried. Patients 18 years or younger with low-risk PTC between 2004 and 2016 were included. Using a 1:1 propensity score matching, patients who underwent TT were matched for age, sex, race, year of diagnosis, and tumor size with a similar cohort of patients who underwent TL. Primary end points were overall survival and disease-specific survival. RESULTS: There were 3,500 patients identified as surgically treated for PTC, of which 1,325 patients met inclusion criteria for matching. Three hundred and twenty-six patients were matched. One hundred and sixty-three patients had TT; 140 were female and mean age was 16 years (interquartile range [IQR] 13 to 17 years). One hundred and sixty-three patients had TL; 140 were female and mean age was 16 years (IQR 14 to 17 years). Median follow-up was 5.0 years (IQR 2.8 to 8 years) and 8.3 years (IQR 3.6 to 14.4 years) in the National Cancer Database and Surveillance, Epidemiology, and End Results cohorts, respectively. There was no statistically significant difference in overall survival or disease-specific survival in patients with PTC < 4 cm, regardless of whether patients underwent TT or TL (p = 0.32 for National Cancer Database registry and p = 0.67 for Surveillance, Epidemiology, and End Results registry). CONCLUSIONS: This study suggests that the extent of thyroidectomy does not influence survival for pediatric patients with early-stage PTC and that TL might be adequate in this patient population.

Response rates in metastatic neuroendocrine tumors receiving peptide receptor radionuclide therapy and implications for future treatment strategies.

BACKGROUND: Peptide receptor radionuclide therapy is a targeted therapy used to treat unresectable somatostatin receptor-positive neuroendocrine tumors. The objective of this study was to evaluate response rates among neuroendocrine tumors of different primaries and identify factors relevant to future treatment strategies. METHODS: We retrospectively reviewed patients who received peptide receptor radionuclide therapy for neuroendocrine tumors from 2018 to 2019 at our institution. Patients were assessed with computed tomography/magnetic resonance imaging and 68Ga-DOTATATE-positron emission tomography before and after 2 or 4 cycles of peptide receptor radionuclide therapy. Tumor response was evaluated by RECIST 1.1. Statistics included multinomial logistic regression models and Fisher exact test. RESULTS: Twenty-seven patients underwent 92 cycles of peptide receptor radionuclide therapy: pancreas (n = 11), small bowel (n = 7), and other (n = 9) neuroendocrine tumors. Overall, 30% (8 of 27) had partial response, 59% (16 of 27) stable disease, and 11% (3 of 27) progressed. Pancreatic neuroendocrine tumors responded differently from small bowel neuroendocrine tumors regardless of cycle number (P = .01). The majority of pancreatic neuroendocrine tumors (6 of 11) had partial response to peptide receptor radionuclide therapy, while all small bowel neuroendocrine tumors had stable disease. Pancreatic neuroendocrine tumors stable after 2 cycles were more likely to respond to additional cycles versus other neuroendocrine tumors (probability: 60% vs 11%). CONCLUSION: Patients with unresectable advanced or metastatic pancreatic neuroendocrine tumors may benefit from a full course of peptide receptor radionuclide therapy, whereas other neuroendocrine tumors appear less likely to respond. Large prospective studies are needed to confirm these findings.

Thyroidectomy for euthyroid patients with Hashimoto thyroiditis and persisting symptoms: A cost-effectiveness analysis.

BACKGROUND: Despite thyroid hormone replacement, some euthyroid patients with Hashimoto thyroiditis will continue to experience persistent symptoms that reduce their quality of life. Recent studies indicate that total thyroidectomy is superior to medical therapy alone in improving these symptoms. However, there is a high complication rate after total thyroidectomy in patients with Hashimoto thyroiditis. This study evaluates the cost-effectiveness of total thyroidectomy for euthyroid patients who have Hashimoto thyroiditis with persistent symptoms. METHODS: We utilized a Markov model to compare total thyroidectomy and medical therapy alone over the lifetime of the cohort. Costs, probabilities, and utility parameters were derived from literature and Medicare cost data. A willingness-to-pay threshold of $100,000/quality-adjusted life years was used. We performed sensitivity analyses to ascertain model uncertainty. RESULTS: On average, medical therapy alone costs $12,845, produced 16.9 quality-adjusted life years, and was dominated. Total thyroidectomy costs $1,490 less and produced 1.4 more quality-adjusted life years. Probabilistic sensitivity analysis confirmed total thyroidectomy as the optimal strategy in 89% of cases. Medical therapy alone will become cost-effective if the cost of uncomplicated thyroidectomy increases by 25%, if the probability of permanent complication after total thyroidectomy increases 12-fold, or if there is no gain in quality of life after thyroidectomy. CONCLUSION: Total thyroidectomy is more cost-effective than medical therapy alone for the management of euthyroid patients who have Hashimoto thyroiditis with persistent symptoms.

Analytical Differences in Intraoperative Parathyroid Hormone Assays.

BACKGROUND: We compared the rates of intraoperative parathyroid hormone (PTH) decline using the Siemens Immulite® Turbo PTH and Roche Elecsys® short turnaround time PTH assays in 95 consecutive surgical patients to investigate analytical and turnaround time (TAT) differences between the tests performed in the operating room (OR) vs the central clinical chemistry laboratory (CCL). METHODS: Serial blood samples from 95 patients undergoing parathyroidectomy were collected and measured using the 2 immunoassays. Specimens from the first 15 patients were measured simultaneously in the OR and CCL and used for the TAT study. In addition to 2 baseline samples, specimens were collected at 5, 10, and 15 min (for some patients, >15 min) after parathyroidectomy. RESULTS: In the TAT study, a significant difference was observed (OR median 20 min vs CCL median 27 min; P < 0.05). Of the 95 patient series, slower rates of parathyroid hormone decrease were observed in approximately 20% of the patients when comparing the Roche with the Immulite immunoassay. CONCLUSIONS: There was a slightly longer TAT in the CCL compared with running the assay directly within the OR (median difference of approximately 7 min). For a majority of the patients, both methods showed equivalent rates of PTH decline; however, for approximately 20% of the patients, there was a slower rate of PTH decline using the Roche assay.

Preoperative calcitriol reduces postoperative intravenous calcium requirements and length of stay in parathyroidectomy for renal-origin hyperparathyroidism.

BACKGROUND: Patients undergoing subtotal parathyroidectomy for renal-origin hyperparathyroidism often develop postoperative hypocalcemia, requiring calcitriol and intravenous calcium (Postop-IVCa). We hypothesized that in subtotal parathyroidectomy for renal-origin hyperparathyroidism, preoperative calcitriol treatment reduces the use of postoperative administration of intravenous calcium. METHODS: A retrospective chart review compared subtotal parathyroidectomy for renal-origin hyperparathyroidism patients who received preoperative calcitriol treatment with those patietns who did not receive preoperative calcitriol treatment at one institution. Preoperative calcitriol treatment loading doses were 0.5 mcg twice daily for 5 days. All patients received postoperative calcitriol and oral calcium carbonate. Postoperative administration of intravenous calcium was given for symptoms, calcium <7.0 mg/dL, or surgeon preference. The Fisher exact test was used to compare proportions. The Wilcoxon test was used to compare continuous data. Multivariable logistic regression adjusted for confounders. RESULTS: Included were 81 patients who received subtotal parathyroidectomy for renal-origin hyperparathyroidism (41 patients who received preoperative calcitriol treatment, 40 patients who did not receive preoperative calcitriol treatment). Preoperative calcitriol treatment use increased over time (0% 2004-2010, 69% 2011-2016). Groups who received preoperative calcitriol treatment and groups who did not receive preoperative calcitriol treatment were similar in preoperative serum calcium, vitamin D, parathyroid hormone, and median age (P > .05 for all). Patients who received preoperative calcitriol treatment less often required postoperative administration of intravenous calcium (34% vs 90% of patients who did not receive preoperative calcitriol treatment, P < .001). Median length of stay was 2.0 days shorter for patients who received preoperative calcitriol treatment versus patients who did not receive preoperative calcitriol treatment patients (P < .001). Factors associated with postoperative administration of intravenous calcium included not receiving preoperative calcitriol treatment, low preoperative calcium, and high preoperative parathyroid hormone. After multivariable adjustment, preoperative calcitriol treatment remained independently associated with reduced postoperative administration of intravenous calcium (OR 0.02, P < .001). CONCLUSION: Preoperative calcitriol therapy lowered use of postoperative administration of intravenous calcium by 56% and length of stay by 50% in subtotal parathyroidectomy for renal-origin hyperparathyroidism patients. We believe preoperative calcitriol treatment should become standard of care for subtotal parathyroidectomy for renal-origin hyperparathyroidism.

Keeping primary aldosteronism in mind: Deficiencies in screening at-risk hypertensives.

BACKGROUND: Primary aldosteronism is a common but underdiagnosed cause of hypertension. Patients with this disorder have worse morbidity compared with those with essential hypertension, but with timely diagnosis and appropriate intervention these patients are potentially cured and may have reversal of target organ damage. The goal of this study was to determine if hypertensive patients considered high risk were checked for primary aldosteronism. METHODS: We reviewed electronic health records to identify patients age 18 years or older with coexisting hypertension and hypokalemia or hypertension and sleep apnea, then determined if they had been investigated with measurement of aldosterone or renin. We built regression models to identify explanatory variables for screening in these 2 high-risk groups. RESULTS: Of nearly 37,000 patients with hypertension and hypokalemia, only 2.7% were ever screened for primary aldosteronism. Most opportunities for case detection were during inpatient hospitalizations, yet in this setting, patients were less likely than clinic patients be screened. Similarly, 3.0% of hypertensive patients with sleep apnea were screened since the inclusion of this group in case detection recommendations. CONCLUSION: Uptake of practice guidelines by hospital physicians, fueled by support from their specialty societies, may help to identify many more patients with unrecognized primary aldosteronism.

Quality of life in thyroid cancer-assessment of physician perceptions.

BACKGROUND: Thyroid cancer is the fastest growing malignancy in the United States. Previous studies have shown a decrease in quality of life (QoL) after the treatment of thyroid cancer. To date, there have been no studies assessing physician perceptions regarding how a diagnosis of thyroid cancer affects QoL. Based on this and other findings from our study, we aim to assess physician perceptions on the effect of thyroid cancer on QoL. MATERIALS AND METHODS: Physicians were recruited from two national organizations comprised physicians focusing on thyroid cancer. A 37-question survey was administered evaluating physician's perceptions of thyroid cancer patient satisfaction in various aspects of treatment, complications, and overall effects on QoL. QoL responses were categorized into overall QoL, physical, psychological, social, and spiritual well-being. RESULTS: One hundred five physicians completed the survey. Physician's estimates of patient's overall QoL after thyroid cancer treatment was similar to overall QoL reported by patients. However, medical physicians overestimated the decrease in thyroid cancer survivor's QoL in several subcategories including physical, psychological, and social (P < 0.05). Both surgeons and medical physicians underestimated the percentage of patients with reported symptoms of temporary and permanent voice changes, temporary dry mouth, cold/heat sensitivity, and temporary and permanent hypocalcemia (P = 0.01-0.04). CONCLUSIONS: Physicians have a varied estimation of the detrimental impact of thyroid cancer treatment on QoL. In addition, physicians underestimated the amount of physical symptoms associated with thyroid cancer treatments. Increased physician awareness of the detrimental effects of a thyroid cancer diagnosis on QoL should allow for a more accurate conversation about expected outcomes after thyroid cancer treatment.

Development of the ThyCAT: A clinically useful computerized adaptive test to assess quality of life in thyroid cancer survivors.

BACKGROUND: Current quality of life assessment tools for thyroid cancer survivors are not clinically useful due to the length of available questionnaires. Computerized adaptive tests are easily administered electronically and can achieve highly accurate and efficient results in minimal time. We aimed to develop a quality of life computerized adaptive tests (ThyCAT) for thyroid cancer survivors. METHODS: A bifactor item response theory model was fit to questionnaire responses from 1,078 North American Thyroid Cancer Survivorship Study participants-a longitudinal cohort study of quality of life in thyroid cancer survivors. Tuning parameters were selected to maintain a correlation of r > 0.9 with the total item bank quality of life score obtained from the original North American Thyroid Cancer Survivorship Study questions, using a minimal number of adaptively administered ThyCAT items. RESULTS: The ThyCAT assesses quality of life with strong correlation (r = 0.96) with the original 75 North American Thyroid Cancer Survivorship Study questions using an average of 9.94 questions (SD ± 3.03) administered in <2 minutes. There was no statistically significant difference in the number of ThyCAT questions required based on demographic or tumor characteristics. CONCLUSION: The ThyCAT can be administered on a smartphone app in <10 questions, and <2 minutes, allowing efficient and accurate in or out of clinic identification of patients struggling with quality of life issues after thyroid cancer treatment.

A Tale of Two Cancers: Traveling to Treat Pancreatic and Thyroid Cancer.

BACKGROUND: Patients diagnosed with a malignancy must decide whether to travel for care at an academic center or receive treatment at a nearby hospital. Here we examine differences in demographics, treatment, and outcomes of those traveling to academic centers for their care vs those not traveling, as well as compare travel for an aggressive vs indolent malignancy. STUDY DESIGN: All patients with papillary thyroid carcinoma (PTC) or pancreatic ductal adenocarcinoma (PDAC) undergoing surgical resection and in the National Cancer Database were examined. Travel for care was abstracted from "crowfly" distance between patients' ZIP codes and treatment facility, region, county size, urban/metro/rural status, and facility type. RESULTS: In total, 105,677 patients with PTC and 22,983 patients with PDAC were analyzed. There were no survival differences by travel in the PTC group. Survival was improved for patients with PDAC traveling from urban/rural settings (hazard ratio = 0.89; 95% CI 0.82 to 0.96; p = 0.002). Patients traveling with PDAC were more likely to have a complete resection and lymph node dissection. Those traveling were less likely to receive chemotherapy or radiotherapy (all p < 0.001). Those traveling with PTC were older, more likely to be male, have Medicare insurance, and had a higher stage of disease (all p < 0.001). Rates of radioactive iodine were lower, American Thyroid Association guidelines were more likely followed, and lymph node dissection was more common for those traveling for care of their PTC (all p < 0.001). CONCLUSIONS: There are improvements in both quality and survival for those traveling to academic centers for their cancer care. In the case of PTC, this difference in quality did not affect overall survival. In PDAC, however, differences in quality translated to a survival advantage.

Ultrasonic, bipolar, and integrated energy devices: comparing heat spread in collateral tissues.

BACKGROUND: Integrated devices incorporating ultrasonic and bipolar technology have been used in laparoscopic surgery, however, are not yet incorporated into open operations. Here, we compare thermal spread and recurrent laryngeal nerve (RLN) functional data of the integrated THUNDERBEAT Open Fine Jaw device, the bipolar Ligasure Small Jaw, and the ultrasonic Harmonic Focus for open thyroidectomy. MATERIALS AND METHODS: The three energy devices were compared in a live porcine model using three tissue types including liver, muscle, and thyroid. The devices were fired three times on each energy setting, and the thermal spread was measured by thermocouples that were inserted in surrounding tissues at 1-mm intervals. To determine RLN injury, devices were fired at successive 1-mm increments from the RLN until the monitor signal was lost. RESULTS: When comparing heat generated across these devices at 1 mm, the peak temperature (Celsius) reached in liver tissue was observed with the ultrasonic device (115.4 ± 86.7), in muscle tissue with the integrated device (104.2 ± 82.1), and in thyroid with the bipolar device (81.4 ± 41.3). Temperatures generated at individual settings on each device were similar (P = 0.11-0.81). RLN injury occurred after firing on manually approximated tissue 1-mm away from the RLN for all devices; however, there was no signal loss at ≥2 mm. CONCLUSIONS: Heat transfer was similar among all devices with the exception of the ultrasonic device when used in the liver, which showed higher temperatures. Liver tissue showed the most consistent results. RLN injury did not occur if the devices were fired on manually approximated tissue ≥2 mm from the nerve.

Thyroid Nodule Size at Ultrasound as a Predictor of Malignancy and Final Pathologic Size.

BACKGROUND: Thyroid-related mortality has remained constant despite the increasing incidence of thyroid carcinoma. Most thyroid nodules are benign; therefore, ultrasound and fine needle aspiration (FNA) are integral in cancer screening. We hypothesize that increased nodule size at ultrasound does not predict malignancy and correlation between nodule size at ultrasound and pathologic exam is good. METHODS: Resected thyroids with preoperative ultrasounds were identified. Nodule size at ultrasound, FNA diagnosis by Bethesda category, size at pathologic examination, and final histologic diagnosis were recorded. Nodule characteristics at ultrasound and FNA diagnoses were correlated with gross characteristics and histologic diagnoses. Nodules for which correlation could not be established were excluded. RESULTS: Of 1003 nodules from 659 patients, 26% were malignant. Nodules <2 cm had the highest malignancy rate (∼30%). Risk was similar (∼20%) for nodules ≥2 cm. Of the 548 subject to FNA, 38% were malignant. Decreasing malignancy rates were observed with increasing size (57% for nodules <1 cm to 20% for nodules >6 cm). At ultrasound size cutoffs of 2, 3, 4, and 5 cm, smaller nodules had higher malignancy rates than larger nodules. Of the 455 not subject to FNA, 11% were malignant. Ultrasound size alone is a poor predictor of malignancy, but a relatively good predictor of final pathologic size (R2 = 0.748), with less correlation at larger sizes. In nodules subject to FNA, false negative diagnoses were highest (6-8%) in nodules 3-6 cm, mostly due to encapsulated follicular variant of papillary carcinoma. CONCLUSIONS: Thyroid nodule size is inversely related to malignancy risk, as larger nodules have lower malignancy rates. However, the relationship of size to malignancy varies by FNA status. All nodules (regardless of FNA status) demonstrate a risk trough at ≥2 cm. Nodules subject to FNA show step-wise decline in malignancy rates by size, demonstrating that size alone should not be considered as an independent risk factor. Size at ultrasound shows relatively good correlation with final pathologic size. False negative rates are low in this series. Lesions with the appropriate constellation of clinical and radiographic findings should undergo FNA regardless of size. Both size and FNA diagnosis should influence the clinical decision-making process.

Rates of secondary hyperparathyroidism after bypass operation for super-morbid obesity: An overlooked phenomenon.

BACKGROUND: With over 110,000 bariatric operations performed in the United States annually, it is important to understand the biochemical abnormalities causing endocrine dysfunction associated with these procedures. Here we compare 2 malabsorptive procedures, duodenal switch and Roux-en-Y gastric bypass, to determine the role malabsorption plays in secondary hyperparathyroidism in this population. METHODS: Data from all super-obese patients undergoing duodenal switch or Roux-en-Y gastric bypass between August 2002 and October 2005 were prospectively collected. Postoperatively, all patients received 1,200 mg of calcium citrate and 1,000 IU vitamin D3 per American Society for Metabolic and Bariatric Surgery guidelines. Beginning in 2007, duodenal switch patients were instructed to add daily vitamin D3 10,000 IU. Statistical analyses included Student t test, multivariate, and univariate logistic regression. RESULTS: Of 283 patients with a body mass index ≥50, 170 (60.1%) underwent duodenal switch, while 113 (39.9%) underwent Roux-en-Y gastric bypass. Of 132 (46.6%) patients with secondary hyperparathyroidism, 101 (59.4%) had undergone duodenal switch and 31 (27.4%) had undergone Roux-en-Y gastric bypass. Symptoms were more common in the duodenal switch group (33 patients [19.4%]) than Roux-en-Y gastric bypass (11 patients [9.7%]). Multivariate logistic regression demonstrated that the extent of bypass and duration of follow-up were the only 2 independent predictive risk factors for developing secondary hyperparathyroidism. Although vitamin D levels improved with increased vitamin D3 supplementation in 2007, rates of secondary hyperparathyroidism increased. CONCLUSION: Despite routine postoperative calcium and vitamin D3 supplementation, secondary hyperparathyroidism is common after Roux-en-Y gastric bypass and duodenal switch. The degree of iatrogenic malabsorption correlates with the incidence of secondary hyperparathyroidism. These rates suggest current supplementation guidelines are not sufficient in preventing secondary hyperparathyroidism. Further work is needed to better define the sequelae of long-term hyperparathyroidism.

Normohormonal primary hyperparathyroidism is a distinct form of primary hyperparathyroidism.

BACKGROUND: Normohormonal primary hyperparathyroidism presents diagnostic and intraoperative challenges, and current literature is conflicting about management. We aim to better define normohormonal primary hyperparathyroidism in order to improve the care for these patients. METHODS: In the study, 516 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidism were divided into 2 groups: classic primary hyperparathyroidism (classic primary hyperparathyroidism, increased serum levels of calcium, and parathyroid hormone) and normohormonal primary hyperparathyroidism (hypercalcemia, normal serum levels of parathyroid hormone). We evaluated inter-group differences in presentation, gland weight, pathology, and complications. RESULTS: The normohormonal primary hyperparathyroidism group was comprised of 116 (22.5%) patients. Mean serum levels of parathyroid hormone and calcium were 62.1 pg/mL ± 10.1 and 10.6 mg/dL ± 0.63 in normohormonal primary hyperparathyroidism, and 142 ± 89.0pg/mL and 11.0 ± 0.88 (both P < .01) for classic primary hyperparathyroidism. Nephrolithiasis was more common in normohormonal primary hyperparathyroidism. Multigland hyperplasia was more common in normohormonal primary hyperparathyroidism 23 (19.8%) vs 44 (11%; P = .04). Concordant imaging studies were less likely in normohormonal primary hyperparathyroidism (82 [73.2%] vs 337 [87.1%; P < .01]), had a lesser total gland weight (531.8 mg ± 680.0 vs 1,039.6 mg ± 1,237.3; P < .01), and lesser 2-week parathyroid hormone (32.5 pg/mL ± 18.95 vs 41.0 pg/mL ± 27.8; P = .01). There was no difference in hypoparathyroidism (parathyroid hormone <15 pg/mL; P = .93) at 2 weeks postoperatively. CONCLUSION: Normohormonal primary hyperparathyroidism represents 22.5% of our primary hyperparathyroidism population, which is greater than reported previously. It is a distinct disease process from classic primary hyperparathyroidism in presentation, imaging, and operative findings. More hyperplasia and a lesser gland weight make it challenging to resect the ideal amount of tissue. Studies with long-term follow-up are needed to determine optimal operative management.

Incidence, Risk Factors, and Clinical Outcomes of Incidental Parathyroidectomy During Thyroid Surgery.

BACKGROUND: The reported rate of incidental parathyroidectomy (IP) during thyroid surgery is between 5.2 and 21.6 %. Current literature reports wide discrepancy in incidence, risk factors, and outcomes. Thus study was designed to address definitively the topic of IP and identify associated risk factors and clinical outcomes with this multi-institutional study. METHODS: This retrospective cohort study included 1767 total thyroidectomies that occurred between 1995 and 2014 at two academic centers. Pathologic reports were reviewed for the presence of unintentionally removed parathyroid glands. Demographics, potential risk factors, and postoperative calcium levels were compared with matched control group. Logistic regression, t tests, and Chi squared tests were used when appropriate. RESULTS: IP occurred in 286 (16.2 %) of thyroidectomies. Risk factors for IP were: malignancy, neck dissection, and lymph node metastases (p = 0.005, <0.001, and <0.001). Fifty-three (19.2 %) of IPs were intrathyroidal. Those with IP were more likely to have postoperative biochemical (65.6 vs. 42.0 %; p < 0.001) and symptomatic (13.4 vs. 8.1 %; p = 0.044) hypocalcemia than controls. The number of parathyroids identified intraoperatively was inversely correlated with the number of parathyroid glands in the specimen (p < 0.001). CONCLUSIONS: Our findings indicate that malignancy, lymph node dissection, and metastatic nodal disease are risk factors for IP. Patients with IP were more likely to have postoperative biochemical and symptomatic hypocalcemia than controls, showing that there is a physiologic consequence to IP. Additionally, intraoperative surgeon identification of parathyroid glands results in a lower incidence of IP, highlighting the importance of awareness of parathyroid anatomy during thyroid surgery.

Radiation-Induced Differentiated Thyroid Cancer Is Associated with Improved Overall Survival but Not Thyroid Cancer-Specific Mortality or Disease-Free Survival.

BACKGROUND: Radiation is a well-described risk factor for differentiated thyroid carcinoma (DTC). Although the natural history of DTC following nuclear disasters and in healthcare workers with chronic radiation exposure (RE) has been described, little is known about DTC following short-term exposure to therapeutic medical radiation for benign disease. This study compares DTC morphology and outcomes in patients with and without a prior history of therapeutic external RE. METHODS: A retrospective review was performed of patients with DTC treated at The University of Chicago between 1951 and 1987, with a median follow-up of 27 years (range 0.3-60 years). Patients were classified as either having (RE+) or not having (RE-) a history of therapeutic RE. Variables examined included sex, age at RE, dose of RE, indication for RE, DTC histology, and outcome. Morphology was determined by blinded retrospective review of all available histologic slides. Outcomes were assessed using Cox proportional hazards model and Kaplan-Meier curves. RESULTS: Of 257 DTC patients, 165 (64%) were RE- and 92 (36%) were RE+, with males comprising a greater proportion of the RE+ group (43.5% vs. 27.3%; p = 0.01). A total of 94.2% of DTC cases were classic papillary cancers; histology did not differ between RE+ and RE- cohorts (p = 0.73). RE was associated with an increased median overall survival (OS; 43 years vs. 38 years; hazard ratio [HR] = 0.55 [confidence interval (CI) 0.34-0.89]; p = 0.01). Survival for males in the RE- group was significantly worse than it was for RE- females (HR = 1.78 [CI 1.05-3.03]; p = 0.03) or RE+ males (HR = 2.98 [CI 1.39-6.38]; p = 0.01). Recurrence did not differ between the RE+ and RE- groups (HR = 0.85 [CI 0.52-1.41]; p = 0.54), nor did DTC-specific mortality (HR = 0.54 [CI 0.21-1.37]; p = 0.20). CONCLUSIONS: While DTC following RE has historically been considered a more aggressive variant than DTC in the absence of RE, the present data indicate that RE+ DTC is associated with better OS than RE- DTC, especially for males. Additionally, recent reports are confirmed of equivalent rates of thyroid cancer recurrence. These results warrant further investigation into the factors underlying this unexpected finding.

Clinical and Pathologic Predictors of Lymph Node Metastasis and Recurrence in Papillary Thyroid Microcarcinoma.

BACKGROUND: The treatment for patients with papillary thyroid microcarcinoma (PTMC) is controversial because PTMC is often found incidentally and its prognosis is very good. Lymph node metastasis (LNM) is one of the main predictors of recurrence and survival. This retrospective study aimed to identify clinical and pathologic factors that increase the risk of metastasis or recurrence, in order to isolate clinically unfavorable PTMCs to help guide therapy. METHODS: Clinical and pathologic data were collected from 273 patients diagnosed with PTMC at The University of Chicago Medical Center between 2000 and 2011. Data points included age, sex, race/ethnicity, tumor size, multifocality, thyroiditis, extrathyroidal extension (ETE), surgical margins, preoperative clinical suspicion of cancer, central/lateral lymph nodes removed and lymph nodes with metastatic carcinoma, treatment, local recurrence, distant recurrence, and survival. RESULTS: Multivariate logistic regression showed that age <45 years (odds ratio [OR] = 3.565 [confidence interval (CI) 1.137-11.177]), multifocality (OR = 3.556 [CI 1.066-11.855]), and ETE (OR = 4.622 [CI = 1.068-20.011]) significantly increased the risk of central LNM (CLNM). However, sex, size of tumor, thyroiditis, positive margins, and clinical suspicion were not correlated with an increased risk for CLNM. Multivariate logistic regression showed that only ETE (OR = 16.066 [CI 1.850-139.488]) significantly increased the risk of lateral LNM. In the cohort of 202 patients with follow-up data, only six recurred. Median time to recurrence was approximately 12 months (range 3.5-120 months), and median follow-up was 42 months. No patient had distant metastasis, and no patients died. CONCLUSIONS: PTMC is an indolent disease, but does pose a risk for LNM and local recurrence. More aggressive treatment or more frequent follow-up could be considered for patients with unfavorable features (age <45 years, multifocality, ETE), especially in the setting of involved lymph nodes at the time of surgical resection, as these patients may be at an increased risk for recurrence.

Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation Analysis.

BACKGROUND: Alterations in DNA methylation have been demonstrated in a variety of malignancies, including papillary thyroid cancer (PTC). The full extent of dysregulation in PTC and the downstream affected pathways remains unclear. Here we report a genome-wide analysis of PTC methylation, the dysregulation of various canonical pathways, and assess its potential as a diagnostic test. METHODS: A discovery set utilized 49 PTCs and matched normal controls from The Cancer Genome Atlas. Another set of 16 PTCs and 13 normal controls were used as a replication set. Genome-wide methylation analysis was done using Illumina 450 K methylation chips. Differentially methylated loci (DML) were identified by comparing PTC and matched normal tissues. DML were defined as false-discovery rate p < 0.05 and absolute Δß ≥ 0.2. DML were then analyzed for pathway and disease commonalities using Qiagen Ingenuity Pathway Analysis. RESULTS: Of 485,577 CpG sites analyzed, 1226 DML were identified in our discovery and replication sets, and 1061 (86.5 %) DML showed hypomethylation when comparing tumor with normal tissue. Support vector machine classification was able to differentiate benign from malignant tissue in 107 (94.7 %) of 113 tested samples, including 15 (83.3 %) of 18 samples lacking a clearly deleterious mutation. Statistically significant associations with multiple canonical pathways, diseases, and biofunctions were observed including PI3K, PTEN, wnt/ß-catenin, and p53. CONCLUSIONS: Epigenetic dysregulation of multiple canonical pathways are associated with the development of PTC. This methylation signature shows promise as a future adjunctive screening test for thyroid nodules.

One-hour PTH after thyroidectomy predicts symptomatic hypocalcemia.

BACKGROUND: A major morbidity after total thyroidectomy is hypocalcemia. Although many clinical factors and laboratory studies have been correlated with both biochemical and symptomatic hypocalcemia, the ideal use and timing of these tests remain unclear. We hypothesize 1-h (PACU) parathyroid hormone (PTH) will identify patients at risk for symptomatic hypocalcemia. METHODS: This prospective study evaluated 196 patients undergoing total thyroidectomy. Serum calcium and PTH levels were measured 1 h after surgery and on postoperative day 1 (POD1). Performance of a central compartment lymph node dissection, parathyroid autotransplantation, indication for procedure, pathology, and presence of parathyroid tissue in the pathology specimen were recorded. RESULTS: Of 196 patients, nine (4.6%) developed symptomatic hypocalcemia. Thirty four (17.3%) had a 1-h PACU PTH ≤10 pg/dL, whereas 31 (15.8%) had a POD1 PTH of ≤10. Five (56%) of the nine symptomatic patients underwent central compartment lymph node dissection, four (44%) had parathyroid autotransplantation, and four (44%) had a PACU PTH ≤10. PACU and POD1 PTH levels were correlated (R(2) = 0.682). Multivariate regression identified central compartment dissection, autotransplantation, and PACU or POD1 PTH correlated with symptomatic hypocalcemia. PACU PTH, POD1 PTH, PACU Ca, malignant final pathology, and age ≤45 y correlated with biochemical hypocalcemia. CONCLUSIONS: A 1-h postoperative PACU PTH is equivalent to POD1 PTH in predicting the development of symptomatic hypocalcemia. Biochemical hypocalcemia was not predictive of symptoms in the immediate postoperative period. Lymph node dissection and parathyroid autotransplantation correlated with symptomatic hypocalcemia and improve the sensitivity of biochemical screening alone.

The Breast-Thyroid Cancer Link: A Systematic Review and Meta-analysis.

Rates of thyroid cancer in women with a history of breast cancer are higher than expected. Similarly, rates of breast cancer in those with a history of thyroid cancer are increased. Explanations for these associations include detection bias, shared hormonal risk factors, treatment effect, and genetic susceptibility. With increasing numbers of breast and thyroid cancer survivors, clinicians should be particularly cognizant of this association. Here, we perform a systematic review and meta-analysis of the literature utilizing PubMed and Scopus search engines to identify all publications studying the incidence of breast cancer as a secondary malignancy following a diagnosis of thyroid cancer or thyroid cancer following a diagnosis of breast cancer. This demonstrated an increased risk of thyroid cancer as a secondary malignancy following breast cancer [OR = 1.55; 95% confidence interval (CI), 1.44-1.67] and an increased risk of breast cancer as a secondary malignancy following thyroid cancer (OR = 1.18; 95% CI, 1.09-1.26). There is a clear increase in the odds of developing either thyroid or breast cancer as a secondary malignancy after diagnosis with the other. Here, we review this association and current hypothesis as to the cause of this correlation.