Making Choices: A Multi-institutional, Longitudinal Cohort Study Assessing Changes in Treatment Outcome Valuation for Low-Risk Thyroid Cancer.

OBJECTIVE: To evaluate the relative importance of treatment outcomes to patients with low-risk thyroid cancer (TC). SUMMARY BACKGROUND DATA: Overuse of total thyroidectomy (TT) for low-risk TC is common. Emotions from a cancer diagnosis may lead patients to choose TT resulting in outcomes that do not align with their preferences. METHODS: Adults with clinically low-risk TC enrolled in a prospective, multi-institutional, longitudinal cohort study from 11/2019-6/2021. Participants rated treatment outcomes at the time of their surgical decision and again 9 months later by allocating 100 points amongst 10 outcomes. T-tests and Hotelling's T 2 statistic compared outcome valuation within and between subjects based on chosen extent of surgery (TT vs. lobectomy). RESULTS: Of 177 eligible patients, 125 participated (70.6% response) and 114 completed the 9-month follow-up (91.2% retention). At the time of the treatment decision, patients choosing TT valued the risk of recurrence more than those choosing lobectomy and the need to take thyroid hormone less ( P <0.05). At repeat valuation, all patients assigned fewer points to cancer being removed and the impact of treatment on their voice, and more points to energy levels ( P <0.05). The importance of the risk of recurrence increased for those who chose lobectomy and decreased for those choosing TT ( P <0.05). CONCLUSION: The relative importance of treatment outcomes changes for patients with low-risk TC once the outcome has been experienced to favor quality of life over emotion-related outcomes. Surgeons can use this information to discuss the potential for asthenia or changes in energy levels associated with total thyroidectomy.

Perception of risk and treatment decisions in the management of differentiated thyroid cancer.

BACKGROUND AND OBJECTIVES: The recent de-escalation of care for differentiated thyroid cancer (DTC) has broadened the range of initial treatment options. We examined the association between physicians' perception of risk and their management of DTC. METHODS: Thyroid specialists were surveyed with four clinical vignettes: (1) indeterminate nodule (2) tall cell variant papillary thyroid cancer (PTC), (3) papillary thyroid microcarcinoma (mPTC), and (4) classic PTC. Participants judged the operative risks and likelihood of structural cancer recurrence associated with more versus less aggressive treatments. A logistic mixed effect model was used to predict treatment choice. RESULTS: Among 183 respondents (13.4% response rate), 44% were surgical and 56% medical thyroid specialists. Risk estimates and treatment recommendation varied markedly in each case. Respondents' estimated risk of 10-year cancer recurrence after lobectomy for a 2.0-cm PTC ranged from 1% to 53% (interquartile range [IQR]: 3%-12%), with 66% recommending lobectomy and 34% total thyroidectomy. Respondents' estimated 5-year risk of metastastic disease during active surveillance of an 0.8-cm mPTC ranged from 0% to 95% (IQR: 4%-15%), with 36% choosing active surveillance. Overall, differences in perceived risk reduction explained 10.3% of the observed variance in decision-making. CONCLUSIONS: Most of the variation in thyroid cancer treatment aggressiveness is unrelated to perceived risk of cancer recurrence.

Trends in Adjuvant External Beam Radiation Therapy for Nonanaplastic Thyroid Cancer in California, 2003-2017.

BACKGROUND: External beam radiation therapy (EBRT) is rarely used to treat patients with differentiated or medullary thyroid cancer. Although EBRT is generally administered to patients with high-risk or unresectable diseases, neither its indications for the use nor the associated outcomes are well-defined. We used a statewide cohort to assess the trends in EBRT use and postradiation outcomes in California. METHODS: A population-based study of patients within the California Cancer Registry who underwent EBRT after surgery for nonanaplastic thyroid cancer (2003-2017) was conducted. The primary outcome was the annual utilization rate of EBRT. The secondary outcomes included Kaplan-Meier analysis for cause-specific survival and identifying factors associated with improved survival after EBRT. RESULTS: Among the 57 607 patients with nonanaplastic thyroid cancer from 2003 to 2017, 344 (0.6%) patients received EBRT. EBRT was utilized in 0.4% of papillary, 1.1% of follicular, and 7.7% of medullary thyroid cancers in California. Overall, 99 (28.8%) patients treated with EBRT died of thyroid cancer. The 10-year cause-specific survival of all patients with thyroid cancer after EBRT was 61.5% (95% CI: 54.8%-69.1%) and that of patients without distant disease was 80.3% (95% CI: 73.5%-87.8%). The survival outcomes varied by tumor size, histology, disease stage, patient age at diagnosis, and the presence of extrathyroidal extension (P < .05). CONCLUSIONS: The use of adjuvant EBRT for nonanaplastic thyroid cancer remained stable and low in California from 2003 to 2017. The comparative efficacy of EBRT was not discernible in this study, but disease control appeared durable in select patients. Well-controlled observational studies and/or prospective studies are needed to better define which patients benefit from EBRT.

Comparison of Preoperative Alpha-blockade for Resection of Paraganglioma and Pheochromocytoma.

OBJECTIVE: Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine. METHODS: We conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs. RESULTS: Twenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin. CONCLUSION: Phenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.

Longitudinal Assessment of Quality of Life Following Molecular Testing for Indeterminate Thyroid Nodules.

BACKGROUND: Molecular testing can refine the risk of malignancy in cytologically indeterminate thyroid nodules and can reduce the need for diagnostic thyroidectomy. However, quality of life (QOL) in patients mananged with molecular testing is not well studied. OBJECTIVE: We aimed to assess the QOL of patients undergoing surveillance after a benign molecular test result, or thyroidectomy after a suspicious molecular test result. METHODS: This prospective longitudinal follow-up of the Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules randomized trial utilized the Thyroid-Related Patient-Reported Outcome, 39-item version (ThyPro-39) to assess the QOL of patients with indeterminate cytology on thyroid fine needle aspiration (FNA) biopsy. All patients underwent molecular testing at the time of initial FNA. A mixed-effect model was used to determine changes in QOL over time. RESULTS: Of 252 eligible patients, 174 completed the assessment (69% response rate). Molecular test results included 72% (n = 124) benign and 28% (n = 50) suspicious. ThyPro-39 scores of benign molecular test patients were unchanged from baseline (following initial FNA and molecular test results) to 18 months of ultrasound surveillance. Baseline symptoms of goiter, anxiety, and depression were more severe for patients with suspicious compared with benign molecular test results. At a median of 8 months after thyroidectomy, suspicious molecular test patients reported improved symptoms of goiter, anxiety, and depression. CONCLUSION: A benign molecular test provides sustained QOL throughout ultrasound surveillance, without worsening anxiety or depression relating to the risk of malignancy. Definitive surgery results in improvement of QOL in patients with suspicious molecular tests.

Normocalcaemic primary hyperparathyroidism: An update on diagnostic and management challenges.

Normocalcaemic primary hyperparathyroidism is a condition that can present with intermittent hypercalcemia or may evolve into hypercalcemic primary hyperparathyroidism. This milder biochemical entity remains incompletely understood because of a lack of long-term health outcomes regarding both medical and surgical approaches to its management. Medical therapies have shown some efficacy. A limited number of studies have found that bisphosphonates increase bone mineral density, and calcimimetics may decrease the risk of nephrolithiasis in patients with normocalcaemic primary hyperparathyroidism. Studies have also described patient outcomes after applying the same surgical criteria used for patients with hypercalcaemic primary hyperparathyroidism to those with the normocalcaemic form of the disease. These studies suggest that parathyroid surgery appears to be effective in normalizing elevated serum parathyroid hormone concentrations and decreasing adverse renal and skeletal outcomes in patients with normocalcaemic hyperparathyroidism. Given the available data and overall lack of consensus regarding the optimal management of these patients, a reasonable approach is to tailor treatment to the individual patient by considering their risk factors for new or accelerated bone loss, kidney stones, diminished quality of life, and cardiovascular disease.

Selective use of Molecular Testing Based on Sonographic Features of Cytologically Indeterminate Thyroid Nodules: A Decision Analysis.

BACKGROUND: Molecular diagnostics can allow some patients with indeterminate thyroid nodule cytopathology to avoid diagnostic hemithyroidectomy; however, the testing is costly. We hypothesized that molecular testing with the intention of preventing unnecessary diagnostic hemithyroidectomy would be cost-effective if this test was applied selectively based on sonographic risk of malignancy. METHODS: A Markov model was constructed depicting a 40-year-old patient with a cytologically indeterminate thyroid nodule. Molecular testing of fine needle aspiration material was compared to a strategy of immediate diagnostic hemithyroidectomy. Data from a single tertiary-referral health system were reviewed to estimate the outcomes of molecular testing of indeterminate nodules stratified by the American Thyroid Association sonographic classification system. Other outcome probabilities and their utilities were derived from literature review. Costs were estimated with Medicare reimbursement data. A $100,000/QALY threshold for cost-effectiveness was applied. Sensitivity analysis was employed to examine uncertainty in the model's assumptions. RESULTS: Of 123 patients who underwent molecular testing for indeterminate cytology, 12 (9.8%) were classified as high sonographic suspicion, 49 (40%) were intermediate suspicion, and 62 (50%) were low or very low suspicion. Molecular testing was only cost-effective when the pretest probability of a negative test was greater than 31%. The model was most sensitive to the cost of molecular testing and the quality adjustment factor for hypothyroidism. CONCLUSIONS: In hypothetical modeling, molecular testing is only cost-effective for cytologically indeterminate thyroid nodules with sonographic features that are intermediate or low suspicion for malignancy. In nodules with high sonographic suspicion, molecular testing is rarely negative and appears to add minimal value.

Quality of Life Following Molecular Marker Testing for Indeterminate Thyroid Nodules.

OBJECTIVE: Thyroid cancer has a disproportionately negative effect on the quality of life (QOL) compared to malignancies with a worse prognosis. The QOL of patients with indeterminate thyroid nodules has not been previously evaluated. We aimed to assess the impact of molecular test results on the QOL of patients with indeterminate thyroid nodules. METHODS: A short version of the Thyroid-Related Patient-Reported Outcome (ThyPro-39) was used to assess the QOL of patients who underwent thyroid fine needle aspiration (FNA) biopsy throughout UCLA Health from May, 2016, to June, 2017. All patients with indeterminate biopsy results underwent molecular testing with either Afirma Gene Expression Classifier or ThyroSeq v2 at the time of the initial biopsy. The QOL associated with symptoms of goiter, anxiety, depression, and impaired daily life were analyzed. RESULTS: Of 825 consented patients, 366 completed the assessment (44.4% response rate). FNA results included 76% benign, 7% malignant, and 17% indeterminate. There were no differences in QOL between patients with a benign FNA and patients with an indeterminate result with benign molecular testing. In patients with an indeterminate FNA, symptoms of goiter (20.5 versus 10.4; P = .033) and depression (33.3 versus 21.0; P = .026) were worse for patients with suspicious versus benign molecular test results; however, no significant differences were observed in anxiety or impaired daily life. CONCLUSION: A benign molecular test result may provide reassurance for patients with indeterminate thyroid nodules that the risk of malignancy is low. Long-term follow-up is necessary to determine if benign molecular test results maintain improved QOL.

Surgery for Primary Hyperparathyroidism: Adherence to Consensus Guidelines in an Academic Health System.

OBJECTIVE: To determine the extent to which consensus guidelines for surgery in patients with primary hyperparathyroidism (PHPT) are followed within an academic health system. BACKGROUND: Previous studies have shown that adherence to consensus guidelines in community practice is low. METHODS: Adults with biochemically confirmed PHPT who received primary care within an academic health system were identified from 2005 to 2015. Multivariable logistic regression was used to analyze predictors of parathyroidectomy (PTx). RESULTS: In 617 patients, the overall PTx rate was 30.8%. When individual consensus criteria were examined, age <50 (P<0.01), serum calcium >11.3 mg/dL (P < 0.01), and hypercalciuria (P = 0.02) were associated with PTx; while nephrolithiasis (P = 0.07) and osteoporosis (P = 0.34) did not affect the PTx rate. The PTx rate increased with the number of consensus criteria satisfied (1 criterion, 33%; 2 criteria, 45%; 3 or more criteria, 82%, P < 0.01). Independent predictors of PTx included male sex [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.8], increasing serum parathyroid hormone (OR 1.1 per 10 pg/mL 95% CI 1.05-1.13), and endocrinologist evaluation (OR 1.6, 95% CI 1.1-2.4); while Black race (OR 0.4, 95% CI 0.2-0.8), lack of 24-hour urine calcium measurement (OR 0.5, 95% CI 0.3-0.8), Charlson Comorbidity Index ≥ 2 (OR 0.6, 95% CI 0.4-0.9), and age ≥80 years (OR 0.2, 95% CI 0.1-0.4) predicted against PTx. CONCLUSION: Within an academic health system, consensus guidelines do appear to influence the decision for surgery in patients with PHPT. However, the level of compliance is generally low, and similar to that observed in community practice.

Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism.

BACKGROUND: Normocalcemic (incipient) primary hyperparathyroidism (PHPT) is characterized by inappropriately elevated parathyroid hormone (PTH) levels in the setting of normal serum calcium. The biochemical and skeletal outcomes after parathyroidectomy for normocalcemic PHPT are not well-described. METHODS: All patients who underwent parathyroidectomy for normocalcemic PHPT at a single institution were retrospectively reviewed (2006-2016). Pre- and postoperative calcium, PTH, and bone mineral density (BMD) were compared between patients with normalized versus persistently elevated PTH levels > 6 months after parathyroidectomy. Multivariable Cox regression was used to identify risk factors associated with persistently elevated PTH levels after parathyroidectomy. RESULT: Parathyroidectomy was performed in 71 patients with normocalcemic PHPT, of whom 38 (53.5%) had multi-gland disease. No patients became hypercalcemic, with a median follow-up of 23.1 months. Persistently elevated PTH levels were noted in 33 (46.5%) patients. In multivariable analysis, preoperative PTH > 100 pg/mL was associated with persistently elevated PTH levels after parathyroidectomy. In 38 patients with available pre- and postoperative BMD measurements, the mean preoperative BMD improved + 5.6% (p < 0.01) in patients with normalized PTH, while no significant change was observed in patients with persistently elevated PTH levels (- 2.2%, p = 0.47). CONCLUSIONS: Elevated PTH levels are common after parathyroidectomy for normocalcemic PHPT. Improvements in BMD may be predicated on long-term normalized PTH levels following surgery.

Risk Factors for Readmission After Parathyroidectomy for Renal Hyperparathyroidism.

BACKGROUND: Patients with renal hyperparathyroidism (RHPT) are susceptible to major electrolyte fluctuations following parathyroidectomy, which may predispose them to early readmission. The purpose of this study is to evaluate risk factors for readmission in patients undergoing parathyroidectomy for RHPT. METHODS: Patients with renal failure who underwent parathyroidectomy were abstracted from the California Office of Statewide Health Planning and Development (1999-2012). Multivariable logistic regression was used to identify risk factors for readmission within 30 days of discharge. RESULTS: The cohort included 4411 patients, of whom 17% were readmitted. Procedures included subtotal parathyroidectomy (74% of cases) and total parathyroidectomy with autotransplantation (26%). Median time to readmission was 9 days (interquartile range 4-16 days). Electrolyte disturbances including hypocalcemia were present in 36% of readmissions and were the most common cause for readmission. Independent risk factors for readmission included Black race [odds ratio (OR) 1.26, 95% confidence interval (CI) 1.00-1.57], Hispanic race (OR 1.38, 95% CI 1.12-1.71), disposition with home health (OR 1.94, 95% CI 1.35-2.77), disposition to a skilled nursing facility (OR 2.30, 95% CI 1.58-3.35), and total parathyroidectomy with autotransplantation (OR 1.27, 95% CI 1.06-1.52). Advancing age (OR 0.98, 95% CI 0.98-0.99) and surgery at a high-volume hospital (OR 0.53, 95% CI 0.36-0.77) were protective against readmission. CONCLUSIONS: Patients undergoing parathyroidectomy for RHPT have a high readmission rate, most frequently for metabolic complications. Increased postoperative vigilance, which may include outpatient laboratory monitoring, may be indicated in patients with risk factors for readmission.

Sustained Growth of a University-Based Endocrine Surgery Program Over 10 Years.

BACKGROUND: Endocrine surgery continues to mature as a subspecialty field. We describe the clinical performance of an academic endocrine surgery program (ESP) over its first 10 years. METHODS: We examined all endocrine procedures performed during the 10-year period (2006-2015) following the inception of the ESP. Institutional and state-level data on case volume, patient geographic origin, and hospital-side costs were obtained. RESULTS: Endocrine case volume increased by approximately ninefold over the study period (from 102 cases in 2006 to 919 cases in 2015). The rate of growth remained approximately linear, and was driven by geographic expansion of referral regions coupled with transitioning low- to moderate-acuity operations to venues outside of the main tertiary care hospital. Market share across the eight-county Southern California region grew by more than twofold over the study period. Increased utilization of outpatient surgery led to cost reductions, averaging 11.1% per case by 2015. CONCLUSIONS: Establishment of an academic ESP can lead to sustained clinical growth and a fundamental shift in regional referral patterns. The nation's continued need for skilled high-volume endocrine surgeons represents opportunities for medical centers to institute their own dedicated endocrine surgery programs.

Single-incision retroperitoneoscopic adrenalectomy: a North American experience.

BACKGROUND: Endoscopic adrenalectomy is currently performed using multiple ports placed either transabdominally or retroperitoneally. We report our initial experience with single-incision retroperitoneoscopic adrenalectomy (SIRA). METHODS: A prospective database of patients undergoing adrenalectomy from December 2013 through March 2016 was analyzed. We adopted conventional retroperitoneoscopic adrenalectomy (CORA) in December 2013 and transitioned to SIRA in March 2015. SIRA was performed using three trocars placed through a single 2-cm incision below the 12th rib. Clinical characteristics and outcomes were compared between patients undergoing SIRA and CORA. RESULTS: One hundred and five adrenalectomies were performed in 102 patients: 34 laparoscopic transperitoneal, 24 CORA, 37 SIRA and 7 open. The SIRA and CORA groups were similar with respect to clinical characteristics (SIRA vs. CORA: mean BMI 27.0 vs. 28.8 kg/m2, maximum BMI 38.9 vs. 44.3 kg/m2; mean nodule size 3.2 vs. 3.2 cm, maximum nodule size 8.0 vs. 6.0 cm). One patient undergoing SIRA required placement of an additional 5-mm port because of extensive adhesions. No patients who underwent SIRA or CORA required conversion to open adrenalectomy. There were no deaths, and blood loss remained <10 mL for all cases. Operative length was similar between SIRA and CORA (105 vs. 92 min, P = 0.26). In multivariable linear regression analysis, nodule size > 5 cm (effect = 1.75, P < 0.001) and pheochromocytoma (effect = 1.30, P = 0.05) were significant predictors of increased operative length for SIRA. BMI and laterality (right vs. left) did not affect operative length. Rates of postoperative temporary abdominal wall relaxation, length of stay and postoperative pain medication use were similar between the two groups. CONCLUSIONS: SIRA is safe and feasible to implement as a refinement of CORA and may be applied to technically challenging cases involving obese patients or large nodules. The use of three ports allows for two-handed dissection, which may shorten the learning curve for many surgeons.

NONOPERATIVE MANAGEMENT OF DIFFERENTIATED THYROID CANCER IN CALIFORNIA: A POPULATION-LEVEL ANALYSIS OF 29,978 PATIENTS.

OBJECTIVE: There has been increasing interest in active surveillance of papillary thyroid microcarcinoma. The objective of this study was to characterize the incidence and outcomes of nonoperatively managed differentiated thyroid cancers (DTCs) in California. METHODS: Biopsy-proven DTCs from the California Cancer Registry were linked to data from the California Office of Statewide Health Planning and Development (2004-2012). Low-risk tumors were defined as localized disease measuring <4 cm without extrathyroidal extension, nodal involvement, or distant metastasis. RESULTS: Of 29,978 patients with DTC, 318 (1.1%) were managed nonoperatively. Compared to operatively managed patients, patients managed nonoperatively were older with more comorbidities, larger tumors (mean size, 2.9 cm vs. 2.0 cm), and an increased rate of distant metastasis (20.4% vs. 3.4%). Independent predictors of nonoperative management included increasing age, larger tumor size, papillary histology, and distant metastases. Of 10,795 patients with low-risk tumors, 161 (1.5%) were managed nonoperatively, with tumor size as follows: <1 cm (15.5%), 1 to 2 cm (50.3%), >2 to 3 cm (24.3%), and >3 to 4 cm (9.9%). There were no disease-specific deaths in the low-risk, nonoperative group (median follow-up [interquar-tile range], 21.3 [5.7 to 51.1] months). The proportion of patients managed nonoperatively remained relatively stable over the study period (mean increase 0.1% per year, P = .09). All P values were <.05 unless otherwise stated. CONCLUSION: The vast majority of patients with DTCs are treated surgically, suggesting active surveillance is rarely practiced in California. Although follow-up was limited, no disease-specific mortality in nonoperatively managed, low-risk DTCs was observed. ABBREVIATIONS: CCI = Charlson Comorbidity Index; CCR = California Cancer Registry; CI = confidence interval; DTC = differentiated thyroid cancer; FTC = follicular thyroid carcinoma; HCC = Hürthle cell carcinoma; IQR = interquartile range; mPTC = papillary thyroid micro-carcinoma; OR = odds ratio; OSPHD = Office of Statewide Health Planning and Development; PTC = papillary thyroid carcinoma.

More Extensive Surgery May Not Improve Survival Over Parathyroidectomy Alone in Parathyroid Carcinoma.

BACKGROUND: Parathyroid carcinoma is a rare cause of hyperparathyroidism. Surgery is the only effective therapy, and en bloc resection has previously been recommended. METHODS: A retrospective cohort study of patients with parathyroid carcinoma in the California Cancer Registry and California Office of Statewide Health Planning and Development database from 1999 to 2012 was performed. Patients were stratified by surgical procedure: parathyroidectomy alone, thyroid resection with en bloc parathyroidectomy, and parathyroidectomy with delayed thyroid resection within 6 months. The primary outcome was overall survival stratified by surgical procedure. Secondary outcomes included perioperative complications within 30 days of initial surgery and disease-related complications. RESULTS: Among our study cohort (n = 136), 60 patients underwent parathyroidectomy alone, 58 patients had en bloc resection, and 18 patients had parathyroidectomy followed by delayed thyroid resection. For the entire cohort, the 5-year and 10-year overall survival rates were 86.9 and 72.0 %. The overall survival rates did not differ between the surgical procedures. Factors that were independently associated with decreased survival included age (hazard ratio 1.05, P = 0.017) and distant metastases (hazard ratio 4.73, P = 0.017), while en bloc resection and delayed thyroid resection were not associated with improved survival over parathyroidectomy alone. There were no differences in perioperative or disease-related complications across procedures. CONCLUSIONS: The addition of thyroid resection to parathyroidectomy may not improve survival for patients with parathyroid carcinoma over complete parathyroid resection alone. A larger prospective study is necessary to determine the optimal treatment to achieve long-term survival with minimal complications.

PRE-ABLATION THYROGLOBULIN AND THYROGLOBULIN TO THYROID-STIMULATING HORMONE RATIO MAY BE ASSOCIATED WITH PULMONARY METASTASES IN CHILDREN WITH DIFFERENTIATED THYROID CANCER.

OBJECTIVE: Pediatric differentiated thyroid cancer (DTC) frequently presents with extensive disease. We studied the value of pre-ablation thyroglobulin (Tg) and Tg normalized to thyroid-stimulating hormone (TSH) levels in predicting distant metastases in pediatric patients with DTC. METHODS: This is a retrospective cohort study of patients <21 years old who underwent thyroidectomy followed by 131I ablation for DTC at 3 university hospitals over 20 years. Tg levels and the Tg/TSH ratio following surgery but prior to 131I ablation were assessed. The presence of distant metastatic disease was determined from the postablation whole-body scan. RESULTS: We studied 44 patients with a mean age of 15.2 years (range 7 to 21 years) and mean tumor size of 2.8 cm. Eight patients had distant metastases and had a higher mean pre-ablation Tg value compared to patients without distant metastases (1,037 µg/L versus 93.5 µg/L, P<.01). The pre-ablation Tg/TSH ratio was also associated with the presence of distant metastases: 12.5 ± 18.8 µg/mU in patients with distant metastases versus 0.7 ± 1.8 µg/mU in patients without (P<.01). A nomogram to predict distant metastases yielded areas under the receiver operating characteristic curve of 0.85 for Tg and 0.83 for Tg/TSH ratio. CONCLUSION: After initial thyroidectomy, elevated preablation Tg and Tg/TSH ratio are associated with distant metastatic disease in pediatric DTC. This may inform the decision to ablate with 131I, as well as the dosage. ABBREVIATIONS: ATA = American Thyroid Association CI = confidence interval DTC = differentiated thyroid cancer OR = odds ratio ROC = receiver operating characteristic Tg = thyroglobulin.

Histopathology of telomerase reverse transcriptase promoter (TERT) mutated indeterminate thyroid nodules.

Objective: The objective of this study was to analyze the risk of malignancy and the histopathology of telomerase reverse transcriptase promoter (TERT) mutated cytologically indeterminate thyroid nodules (ITN). Methods: A PUBMED search of molecularly tested ITN was conducted and data on TERT mutated ITN with histopathology correlation were extracted. Results: Twenty-six manuscripts (published between 2014 and 2022) reported on 77 TERT mutated ITN. Sixty-five nodules were malignant (84 %), with 16 (25 %) described with high-risk histopathology, 5 (8 %) described as low-risk, and most without any description. Isolated TERT mutations were malignant in 26/30 ITNs (87 %) with 9 (35 %) described as high risk and none described as low risk. TERT + RAS mutated ITNs were malignant in 29/34 ITNs (85 %) with 3 (10 %) described as high risk and 4 (14 %) described as low risk. Finally, all 5 TERT + BRAFV600E mutated nodules were malignant and 3/5 (60 %) were described as high risk. Conclusion: TERT mutated ITNs have a high risk of malignancy (84 %), and the current data does not show a difference in malignancy rate between isolated TERT mutations and TERT + RAS co-mutated ITNs. When described, TERT + RAS co-mutated ITNs did not have a higher rate of high-risk histopathology as compared to isolated TERT mutated lesions. Most TERT mutated ITNs did not have a description of histopathology risk and the oncologic outcomes, including rate of recurrence, metastases, and disease specific survival, are unknown. Further data is needed to determine if TERT mutated ITNs should be subjected to aggressive initial treatment.

Outcomes of cytologically indeterminate thyroid nodules managed with Genomic Sequencing Classifier.

CONTEXT: Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery. OBJECTIVE: This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing. DESIGN, SETTING, PATIENTS, AND INTERVENTION: Adult patients who underwent a biopsy at three major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity, specificity, PPV, and NPV of GSC in Bethesda III and IV nodules. RESULTS: The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC's sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance. CONCLUSIONS: GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.