A Dwindling Matter: An Analysis of Medicare Reimbursement for Endocrine Surgery Procedures from 2000-23.

OBJECTIVE: To evaluate Medicare reimbursement trends for endocrine surgeries from 2000-23. BACKGROUND: As the population ages, demand for endocrine surgeries is expected to increase. Understanding reimbursement trends is essential to ensure the financial sustainability of endocrine surgery. METHODS: Data were extracted from Medicare Inpatient and Outpatient Hospital datasets, National Summary, and Physician Fee Look-up Files for nine common thyroid, parathyroid and adrenal surgeries. Data were adjusted for inflation. Descriptive statistics, compound annual growth rate (CAGR), and linear regression models were built to evaluate practice and reimbursement trends. RESULTS: From 2000-23, there was a 63.8% increase in endocrine surgery volume. However, inflation-adjusted average procedure reimbursements decreased by 43.2% from $1709 to $972 (CAGR -2.4%), which is the largest decrease for any surgical subspecialty reported in the published literature. At the current CAGR, the average estimated reimbursement is projected to decrease to $868 by 2030 (P<0.001). Average facility reimbursements for inpatient and outpatient hospitalizations increased. However, substantial practice pattern shifts in the study period led to decreased overall facility reimbursements, with a $17.9 million decrease in total inpatient reimbursements between 2016-21 that was only partially offset by a $3.2 million increase in outpatient hospital reimbursements. CONCLUSION: Medicare procedure reimbursements for endocrine surgeries have been outpaced by inflation, with large decreases since 2000. Concurrent changes in practice patterns have also resulted in markedly fewer inpatient stays leading to lower total facility reimbursements. Our data raise concern over the financial sustainability of the endocrine surgery field as the demand for endocrine surgery procedures increases.

Guideline Adherence and Practice Patterns in the Management of Medullary Thyroid Cancer.

INTRODUCTION: Little is known about nationwide practice patterns for the management medullary thyroid cancer (MTC) in relation to the 2015 American Thyroid Association guidelines and their impact on survival. METHODS: Using the Surveillance, Epidemiology, and End Results Program database (2000-2018), MTC treatment patterns were evaluated in terms of adherence to the 2015 American Thyroid Association guidelines across three time periods (2000-2009, 2010-2015, and 2016-2018). Outcomes of interest were guideline concordance, treatment utilization trends, disease-specific survival (DSS), and overall survival (OS). RESULTS: A total of 3332 patients with MTC were identified. Of which, 53.8%, 33.2%, and 11.4% of patients had localized, regional, and distant disease, respectively. In patients with locoregional disease, the rate of guideline-concordant surgery improved over time from 63.0% in 2000-2009 to 76.0% in 2016-2018 (P < 0.001). Guideline-concordant care was associated with increased OS (HR = 1.85, 95% CI: 1.42-2.43, P < 0.001) in patients with localized disease and increased DSS (HR = 1.65, 95% CI: 1.01-2.54, P < 0.001) and OS (HR = 1.89, 95% CI: 1.35-2.58, P < 0.001) in patients with regional disease. The median OS and DSS in patients with distant disease were 31 and 55 mo, respectively, and the rate of chemotherapy use rose from 21.6% to 39.2% (P = 0.003). CONCLUSIONS: The rate of guideline-concordant surgery for locoregional MTC increased after guideline publication in 2015, with an observed prolongment in OS and DSS. Chemotherapy use among patients with distant disease has increased over time, but their prognosis remains variable.

Salvage Cryoablation for Local Recurrences of Thyroid Cancer Inseparable from the Trachea and Neurovascular Structures.

PURPOSE: To demonstrate safety, feasibility, and effectiveness of cryoablation of recurrent papillary thyroid cancer ineligible for reoperation because of scarring, eligible for focal ablation as defined within 2015 American Thyroid Association guideline sections C16 and C17. MATERIALS AND METHODS: With multidisciplinary consensus, cryoablation was performed with curative intent for 15 tumors in 10 patients between January 2019 and July 2021. Demographics, procedural details, and serial postprocedural imaging findings were analyzed. RESULTS: The mean age was 72.5 years (range, 57-88 years), and 80% of the patients were women. The tumors (mean size, 16 mm ± 6; range, 9-29 mm) received 1 session of cryoablation with 100% technical success. The mean and median postcryoablation tumor volumetric involution rates were 88% and 99%, respectively, with 9 (60%) of 15 tumors involuting completely or down to the scar and 6 (40%) involuting partially at the end of the study period. Tumor size did not increase after cryoablation (0% local progression rate). All tumors abutted the trachea, skin, and/or vascular structures, and hydrodissection failed in all cases because of scarring. The major adverse event rate was 20% (3/15), with 2 cases of voice change and 1 case of Horner syndrome; all resolved at 6 months with no permanent sequelae. No vascular, tracheal, dermal, or infectious adverse events occurred during a mean follow-up of 242 days (range, 114-627 days). One patient died at 386 days after cryoablation because of unrelated cholangiocarcinoma. CONCLUSIONS: Cryoablation of local recurrences of papillary thyroid cancer abutting the trachea and/or neurovascular structures in the setting of hydrodissection failure because of scarring yielded a mean volumetric involution of 88%, primary efficacy of 60%, and objective response rate of 100% with no local recurrences or permanent complications during a mean follow-up of 242 days. The secondary efficacy and longer-term outcomes remain forthcoming.

Severe Hypocalcemia After Thyroidectomy: An Analysis of 7366 Patients.

OBJECTIVE: The aim of the study was to determine severe hypocalcemia rate following thyroidectomy and factors associated with its occurrence. BACKGROUND: Hypocalcemia is the most common complication after thyroidectomy. Severe post-thyroidectomy hypocalcemia can be life-threatening; data on this specific complication are scarce. METHODS: Patients who underwent thyroidectomy in the American College of Surgeons-National Surgical Quality Improvement Program thyroidectomy-targeted database (2016-2017) were abstracted. A severe hypocalcemic event was defined as hypocalcemia requiring intravenous calcium, emergent clinic/hospital visit, or a readmission for hypocalcemia. Multivariable regression was used to identify factors independently associated with occurrence of severe hypocalcemia. RESULTS: Severe hypocalcemia occurred in 5.8% (n = 428) of 7366 thyroidectomy patients, with 83.2% necessitating intravenous calcium treatment. Rate of severe hypocalcemia varied by diagnosis and procedure (0.5% for subtotal thyroidectomy to 12.5% for thyroidectomy involving neck dissections). Overall, 38.3% of severe hypocalcemic events occurred after discharge; in this subset, 59.1% experienced severe hypocalcemia despite being discharged with calcium and vitamin D. Severe hypocalcemia patients had higher rates of recurrent laryngeal nerve injury (13.4% vs 6.6%), unplanned reoperations (4.4% vs 1.3%), and longer hospital stay (30.4% vs 6.2% ≥3 days (all P < 0.01). After multivariate adjustment, severe hypocalcemia was associated with multiple factors including Graves disease [odds ratio (OR) = 2.06], lateral neck dissections (OR: 3.10), and unexpected reoperations (OR = 3.55); all P values less than 0.01. CONCLUSIONS: Severe hypocalcemia and suboptimal hypocalcemia management after thyroidectomy are common. Patients who experienced severe hypocalcemia had higher rates of nerve injury and unexpected reoperations, indicating surgical complexity and provider inexperience. More biochemical surveillance particularly a parathyroid hormone-based protocol, fine-tuned supplementation, and selective referral could reduce occurrence of this morbid complication.

Postoperative Surveillance in Older Adults With T1N0M0 Low-risk Papillary Thyroid Cancer.

BACKGROUND: The frequency and cost of postoperative surveillance for older adults (>65 y) with T1N0M0 low-risk papillary thyroid cancer (PTC) have not been well studied. METHODS: Using the SEER-Medicare (2006-2013) database, frequency and cost of surveillance concordant with American Thyroid Association (ATA) guidelines (defined as an office visit, ≥1 thyroglobulin measurement, and ultrasound 6- to 24-month postoperatively) were analyzed for the overall cohort of single-surgery T1N0M0 low-risk PTC, stratified by lobectomy versus total thyroidectomy. RESULTS: Majority of 2097 patients in the study were white (86.7%) and female (77.5%). Median age and tumor size were 72 y (interquartile range 68-76) and 0.6 cm (interquartile range 0.3-1.1 cm), respectively; 72.9% of patients underwent total thyroidectomy. Approximately 77.5% of patients had a postoperative surveillance visit; however, only 15.9% of patients received ATA-concordant surveillance. Patients who underwent total thyroidectomy as compared with lobectomy were more likely to undergo surveillance testing, thyroglobulin (61.7% versus 24.8%) and ultrasound (37.5% versus 29.2%) (all P < 0.01), and receive ATA-concordant surveillance (18.5% versus 9.0%, P < 0.001). Total surveillance cost during the study period was $621,099. Diagnostic radioactive iodine, ablation, and advanced imaging (such as positron emission tomography scans) accounted for 55.5% of costs ($344,692), whereas ATA-concordant care accounted for 44.5% of costs. After multivariate adjustment, patients who underwent total thyroidectomy as compared with lobectomy were twice as likely to receive ATA-concordant surveillance (adjusted odds ratio 2.0, 95% confidence interval: 1.5-2.8, P < 0.001). CONCLUSIONS: Majority of older adults with T1N0M0 low-risk PTC do not receive ATA-concordant surveillance; discordant care was costly. Total thyroidectomy was the strongest predictor of receiving ATA-concordant care.

Impact of Micro- and Macroscopically Positive Surgical Margins on Survival after Resection of Adrenocortical Carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare, aggressive cancer; complete surgical resection offers the best chance for long-term survival. The impact of surgical margin status on survival is poorly understood. Our objective was to determine the association of margin status with survival. METHODS: Patients with ACC were identified from the National Cancer Data Base, 1998-2012, and stratified based on surgical margin status (negative vs. microscopically positive [+] vs. macroscopically [+]). Univariate/multivariate regression/survival analyses were utilized to determine factors associated with margin status and overall survival (OS). RESULTS: A total of 1553 patients underwent surgery at 589 institutions: 86% had negative, 12% microscopically (+), and 2% macroscopically (+) margins. Those with microscopically (+) and macroscopically (+) margins more often received adjuvant chemotherapy (39.4% macroscopically (+) vs. 38.5% microscopically (+) vs. 25.2% negative margins, p < 0.001). For unadjusted analysis, there was a significant difference in OS between the groups (log-rank p < 0.001), with median survival times of 58 months (95% confidence interval [CI] 49-66) for those with negative margins, 22 months (95% CI 18-34) microscopically (+), and 14 months (95% CI 6-27) macroscopically (+) margins. After adjustment, both microscopically (+) (HR 1.76, p < 0.001) and macroscopically (+) (HR 2.10, p = 0.0019) margin status were associated with compromised survival. CONCLUSIONS: Having micro- or macroscopically (+) margin status after ACC resection is associated with dose-dependent compromised survival. These results underscore the importance of achieving negative surgical margins for optimizing long-term patient outcomes.

Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients.

OBJECTIVES: To correlate thyroid cancer genotype with histology and outcomes. BACKGROUND: The prognostic significance of molecular signature in thyroid cancer (TC) is undefined but can potentially change surgical management. METHODS: We reviewed a consecutive series of 1510 patients who had initial thyroidectomy for TC with routine testing for BRAF, RAS, RET/PTC, and PAX8/PPARG alterations. Histologic metastatic or recurrent TC was tracked for 6 or more months after oncologic thyroidectomy. RESULTS: Papillary thyroid cancer (PTC) was diagnosed in 97% of patients and poorly differentiated/anaplastic TC in 1.1%. Genetic alterations were detected in 1039 (70%); the most common mutations were BRAFV600E (644/1039, 62%), and RAS isoforms (323/1039, 31%). BRAFV600E-positive PTC was often conventional or tall cell variant (58%), with frequent extrathyroidal extension (51%) and lymph node metastasis (46%). Conversely, RAS-positive PTC was commonly follicular variant (87%), with infrequent extrathyroidal extension (4.6%) and lymph node metastasis (5.6%). BRAFV600E and RET/PTC-positive PTCs were histologically similar. Analogously, RAS and PAX8/PPARG-positive PTCs were histologically similar. Compared with RAS or PAX8/PPARG-positive TCs, BRAFV600E or RET/PTC-positive TCs were more often associated with stage III/IV disease (40% vs 15%, P < 0.001) and recurrence (10% vs 0.7%, P < 0.001; mean follow-up 33 ± 21 mo). Distant metastasis was highest in patients with RET/PTC-positive TC (10.8%, P = 0.02). CONCLUSIONS: In this large study of prospective mutation testing in unselected patients with TC, molecular signature was associated with distinctive phenotypes including cancers, with higher risks of both distant metastasis and early recurrence. Preoperative genotype provides valuable prognostic data to appropriately inform surgery.

Adrenal Imaging Features Predict Malignancy Better than Tumor Size.

INTRODUCTION: In adrenal tumors, size ≥ 4 cm has been an indication for adrenalectomy due to concern for malignancy. We compared mass size to imaging features (ImF) for accuracy in diagnosing adrenal malignancy. METHODS: Data were retrieved for 112 consecutive patients who had adrenalectomy from January 2011 to August 2014. ImF was classified as nonbenign if HU > 10 on unenhanced CT scan or if loss of signal on out-of-phase imaging was absent on chemical-shift MRI. Indications for resection included hormonal hypersecretion, nonbenign ImF, and/or size ≥ 4 cm. RESULTS: Of 113 resected adrenals, 37 % were functional. Histologic malignancy occurred in 18 % (20/113) and included 3 adrenocortical carcinomas (ACC), 1 epithelioid liposarcoma, 1 lymphoma, 1 malignant nerve sheath tumor, and 14 adrenal metastases. Patients with malignancies were older (mean age, 60 ± 13 vs. 51 ± 14 years, p = 0.01). Malignant tumors were larger on preoperative imaging (mean 5.3 ± 3.2 vs. 3.9 ± 2.4 cm, p = 0.03). All 20 malignant masses had nonbenign ImF. In predicting malignancy, the sensitivity, specificity, NPV, and PPV of nonbenign ImF was 100, 57, 100, and 33 %, respectively. Size ≥ 4 cm was less predictive with sensitivity, specificity, NPV, and PPV of 55, 61, 86, and 23 %, respectively. If size ≥ 4 cm had been used as the sole criterion for surgery, 45 % of malignancies (9/20) would have been missed including 8 metastases and an ACC. CONCLUSIONS: In resected adrenal tumors, the presence of nonbenign ImF is more sensitive for malignancy than mass size (100 vs. 55 %) with equivalent specificity. Regardless of mass size, adrenalectomy should be strongly considered when non-benign ImF are present.

A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy.

OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.

The small abnormal parathyroid gland is increasingly common and heralds operative complexity.

BACKGROUND: Over decades, improvements in presymptomatic screening and awareness of surgical benefits have changed the presentation and management of primary hyperparathyroidism (PHPT). Unrecognized multiglandular disease (MGD) remains a major cause of operative failure. We hypothesized that during parathyroid surgery the initial finding of a mildly enlarged gland is now frequent and predicts both MGD and failure. METHODS: A prospective database was queried to examine the outcomes of initial exploration for sporadic PHPT using intraoperative PTH monitoring (IOPTH) over 15 years. All patients had follow-up ≥6 months (mean = 1.8 years). Cure was defined by normocalcemia at 6 months and microadenoma by resected weight of <200 mg. RESULTS: Of the 1,150 patients, 98.9 % were cured and 15 % had MGD. The highest preoperative calcium level decreased over time (p < 0.001) and varied directly with adenoma weight (p < 0.001). Over time, single adenoma weight dropped by half (p = 0.002) and microadenoma was increasingly common (p < 0.01). MGD risk varied inversely with weight of first resected abnormal gland. Microadenoma required bilateral exploration more often than macroadenoma (48 vs. 18 %, p < 0.01). When at exploration the first resected gland was <200 mg, the rates of MGD (40 vs. 11 %, p = 0.001), inadequate initial IOPTH drop (67 vs. 79 %, p = 0.002), operative failure (6.6 vs. 0.7 %, p < 0.001), and long-term recurrence (1.6 vs. 0.3 %, p = 0.007) were higher. CONCLUSIONS: Single parathyroid adenomas are smaller than in the past and require more complex pre- and intraoperative management. During exploration for sporadic PHPT, a first abnormal gland <200 mg should heighten suspicion of MGD and presages a tenfold higher failure rate.

The final intraoperative parathyroid hormone level: how low should it go?

BACKGROUND: In minimally invasive surgery for primary hyperparathyroidism (HPT), intraoperative parathyroid hormone (IOPTH) monitoring assists in obtaining demonstrably better outcomes, but optimal criteria are controversial. METHODS: The outcomes of 1,108 initial parathyroid operations for sporadic HPT using IOPTH monitoring from 1997 to 2011 were stratified by final post-resection IOPTH level. All patients had adequate follow-up to verify cure. RESULTS: With mean follow-up of 1.8 years (range 0.5-14.3 years), parathyroidectomy using IOPTH monitoring failed in 1.2 % of cases, with an additional 0.5 % incidence of long-term recurrence at a mean of 3.2 years (range 0.8-6.8 years) postoperatively. Operative success was equally likely with a final IOPTH drop to 41-65 pg/mL vs ≤40 pg/mL (p = 1). In the 76 patients with an elevated baseline IOPTH level that did not drop to ≤65 pg/mL, surgical failure was 43 times more likely than with a drop into normal range (13 vs. 0.3 %; p < 0.001). When the final IOPTH level dropped by >50 % but not into the normal range, surgical failure was 19 times more likely (3.8 vs. 0.2 %; p = 0.015). Long-term recurrence was more likely in patients with a final IOPTH level of 41-65 pg/mL than with a level ≤40 pg/mL (1.2 vs. 0; p = 0.016). CONCLUSIONS: Adjunctive intraoperative PTH monitoring facilitates a high cure rate for initial surgery of sporadic primary hyperparathyroidism. A final IOPTH level that is within the normal range and drops by >50 % from baseline is a strong predictor of operative success. Patients with a final IOPTH level between 41-65 pg/mL should be followed beyond 6 months for long-term recurrence.

Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer?

BACKGROUND: Whether a threshold nodule size should prompt diagnostic thyroidectomy remains controversial. We examined a consecutive series of patients who all had thyroidectomy for a ≥4 cm nodule to determine (1) the incidence of thyroid cancer (TC) and (2) if malignant nodules could accurately be diagnosed preoperatively by ultrasound (US), fine needle aspiration biopsy (FNAB) cytology and molecular testing. METHODS: As a prospective management strategy, 361 patients with 382 nodules ≥4 cm by preoperative US had thyroidectomy from 1/07 to 3/12. RESULTS: The incidence of a clinically significant TC within the ≥4 cm nodule was 22 % (83/382 nodules). The presence of suspicious US features did not discriminate malignant from benign nodules. Moreover, in 86 nodules ≥4 cm with no suspicious US features, the risk of TC within the nodule was 20 %. US-guided FNAB was performed for 290 nodules, and the risk of malignancy increased stepwise from 10.4 % for cytologically benign nodules, 29.6 % for cytologically indeterminate nodules and 100 % for malignant FNAB results. Molecular testing was positive in 9.3 % (10/107) of tested FNAB specimens, and all ten were histologic TC. CONCLUSIONS: In a large consecutive series in which all ≥4 cm nodules had histology and were systematically evaluated by preoperative US and US-guided FNAB, the incidence of TC within the nodule was 22 %. The false negative rate of benign cytology was 10.4 %, and the absence of suspicious US features did not reliably exclude malignancy. At minimum, thyroid lobectomy should be strongly considered for all nodules ≥4 cm.

Outcome and prognostic factors after adrenalectomy for patients with distant adrenal metastasis.

BACKGROUND: The purpose of this study was to describe a single-institution experience with adrenal metastasectomy and to elucidate factors that may bear prognostic significance. METHODS: This is a single-center, retrospective review of patients with adrenal metastasis who underwent adrenalectomy performed with curative intent between 2000 and 2012. The Kaplan-Meier method was used to evaluate overall survival from time of adrenalectomy to death or last follow-up. Primary endpoint was death from any cause. Clinical variables were examined for association with survival. RESULTS: The study included 62 patients with mean age of 60 (±12) years; 55 % (34 of 62) were male, 85 % (53 of 62) presented with isolated adrenal metastasis, and 82 % (51 of 62) had metachronous disease with median disease-free interval (DFI) of 22 months (range, 6-217 months). Non-small cell lung cancer (NSCLC) was the most common primary comprising 50 % of cases. Median survival for the study population was 30 months (range, 1-145 months) and 5-year survival was 31 %. Patients with NSCLC had significantly shortened survival compared with non-NSCLC with median and 5-year survival of 17 versus 47 months and 27 % versus 38 %, respectively (p = .033). Synchronous metastasis (p = .028) and DFI < 12 months (p = .038) were also associated with worse survival outcome, though male gender (p = .69) and oligometastatic disease (p = .62) were not. CONCLUSIONS: Adrenal metastasectomy resulted in median survival of 30 months and 5-year survival of 31 %. Shorter survival was associated with lung primary, short disease-free interval, and synchronous metastasis, but not with the presence of oligometastatic disease provided that the primary cancer and additional metastatic lesions were adequately controlled and amenable to resection.

BRAF V600E mutation independently predicts central compartment lymph node metastasis in patients with papillary thyroid cancer.

PURPOSE: This study was designed to examine whether available preoperative clinical parameters, including B-type Raf kinase (BRAF) V600E mutation status, can identify patients at risk for central compartment lymph node metastasis (CLNM). METHODS: Under an institutional review board-approved protocol, we conducted a single-center, retrospective review of all patients who had initial thyroidectomy for histologic papillary thyroid carcinoma (PTC) during 2010. The presence of CLNM was examined for correlation with available preoperative clinical parameters, including tumor size, gender, age, and BRAF mutation status. RESULTS: Cervical lymph node resection and molecular testing on FNAB or histopathologic specimen was performed on a consecutive series of 156 study patients with histologic PTC. Overall, CLNM was diagnosed in 37% and 46% were BRAF-mutation-positive. BRAF positivity was the only clinical parameter associated with CLNM (BRAF, p=0.002; tumor size≥2 cm, p=0.16; male gender, p=0.1; age≥45 years, p=0.3) and remained an independent predictor of CLNM on multiple logistic regression analysis (odds ratio (OR) 3.2, p=0.001). The PPV and NPV of BRAF positivity for CLNM was 50 and 74%, respectively. When restricting the analysis to the subset of 38 patients who had molecular testing performed preoperatively on FNAB, the PPV and NPV of BRAF positivity for CLNM was 47 and 91%, respectively, and BRAF positivity was still a significant predictor of CLNM on both univariate (OR 8.4, p=0.01) and multivariate (OR 9.7, p=0.02) analyses. CONCLUSIONS: Of the commonly used clinical parameters available preoperatively, the BRAF V600E mutation is the only independent predictor of CLNM in PTC and can be utilized to guide the extent of initial surgery.

Medullary thyroid cancer with RET V804M mutation: more indolent than expected?

BACKGROUND: Significant genotype-phenotype variability among multiple endocrine neoplasia type 2A patients with a RET V804M mutation has been reported. METHODS: Patients with a RET V804M mutation treated at a single center were identified (January 1996-December 2020). The baseline characteristics, operative details, pathology, biochemical, and long-term data were analyzed. RESULTS: There were 79 patients; none developed pheochromocytoma or hyperparathyroidism or died in the study period. The mean age was 41.5 years (range = 1.0-81.0 years); 46.8% were men. Of 68 surgical patients, 53 (77.9%) underwent total thyroidectomy and 15 (22.1%) underwent total thyroidectomy with central neck dissection with or without lateral neck dissection. Twenty-four patients had elevated preoperative calcitonin, of whom 12 underwent total thyroidectomy (median = 7.5; range = 5.0-237.0 pg/mL), 10 underwent total thyroidectomy + central neck dissection (median = 27.6; range = 5.1-147.0 pg/mL), and 2 underwent total thyroidectomy + central neck dissection + lateral neck dissection (median = 3182.0; range = 361.0-6003.0 pg/mL). Pathology was benign (27.9%), papillary thyroid cancer alone (1.5%), C-cell hyperplasia (23.5%), and medullary thyroid cancer (47.1%; median tumor size = 3.0 mm). Three patients had elevated calcitonin postoperatively (median follow-up time = 60.0 months). In adjusted modeling, a preoperative calcitonin >5 pg/mL was associated with having medullary thyroid cancer on final pathology (odds ratio = 13.3; 95% confidence interval, 3.2-56.3; P < .001). CONCLUSION: In this large United States cohort of surgical patients with a RET V804M mutation, most had indolent disease and were without classic multiple endocrine neoplasia type 2A features. Calcitonin >5 pg/mL may serve as a meaningful value to guide surveillance and timing of surgery.

A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma.

BACKGROUND: Thyroid papillary microcarcinoma (TPMC) is an incidentally discovered papillary carcinoma that measures ≤1.0 cm in size. Most TPMCs are indolent, whereas some behave aggressively. The objective of the study was to evaluate whether the combination of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and specific histopathologic features allows risk stratification of TPMC. METHODS: A group aggressive TPMCs was selected based on the presence of lymph node metastasis or tumor recurrence. Another group of nonaggressive tumors included TPMCs matched with the first group for age, sex, and tumor size, but with no extrathyroid spread. A molecular analysis was performed, and histologic slides were scored for multiple histopathologic criteria. A separate validation cohort of 40 TPMCs was evaluated. RESULTS: BRAF mutations were detected in 77% of aggressive TPMCs and in 32% of nonaggressive tumors (P = .001). Several histopathologic features differed significantly between the groups. By using multivariate regression analysis, a molecular-pathologic (MP) score was developed that included BRAF status and 3 histopathologic features: superficial tumor location, intraglandular tumor spread/multifocality, and tumor fibrosis. By adding the histologic criteria to BRAF status, sensitivity was increased from 77% to 96%, and specificity was increased from 68% to 80%. In the independent validation cohort, the MP score stratified tumors into low-risk, moderate-risk, and high-risk groups with the probability of lymph node metastases or tumor recurrence in 0%, 20%, and 60% of patients, respectively. CONCLUSIONS: BRAF status together with several histopathologic features allowed clinical risk stratification of TPMCs. The combined MP risk stratification model was a better predictor of extrathyroid tumor spread than either mutation or histopathologic findings alone.

Outcomes of concurrent parathyroidectomy and thyroidectomy among CESQIP surgeons.

BACKGROUND: Studies comparing endocrine-specific outcomes following parathyroidectomy (PTx) versus concurrent parathyroidectomy and thyroidectomy (PTx + Tx) are few. METHODS: 10,019 patients were selected from the Collaborative Endocrine Surgery Quality Improvement Program (2014-2019). Baseline characteristics and short-term (≤30 days) outcomes for PTx + Tx vs PTx patients were compared using bivariate and multivariable methods. RESULTS: PTx + Tx patients were more likely to experience clinical hypoparathyroidism (6.7% vs 0.5%, p < 0.001), recurrent laryngeal nerve transection, (0.4% vs 0.1%, p = 0.002) and hematoma requiring evacuation (1.0% vs 0.2%, p < 0.001). Readmissions and ED visits for hypocalcemia were more frequent after PTx + Tx vs PTx. Concurrent surgery was associated with an 8-fold increase in risk of short-term complications (Odds Ratio (OR): 8.0, 95% Confidence Interval (CI): 5.7-11.1, p < 0.001). CONCLUSIONS: Patients undergoing PTx + Tx have increased rates of postoperative complications, ED visits, and readmissions compared to patients undergoing parathyroidectomy alone. These findings could help guide surgeon-patient discussions on the risks of concurrent surgery.

Patient-Reported Outcomes Following Total Thyroidectomy for Graves' Disease.

Background: Graves' disease accounts for ∼80% of all cases of hyperthyroidism and is associated with significant morbidity and decreased quality of life. Understanding the association of total thyroidectomy with patient-reported quality-of-life and thyroid-specific symptoms is critical to shared decision-making and high-quality care. We estimate the change in patient-reported outcomes (PROs) before and after surgery for patients with Graves' disease to inform the expectations of patients and their physicians. Methods: PROs using the MD Anderson Symptom Inventory (MDASI) validated questionnaire were collected prospectively from adult patients with Graves' disease from January 1, 2015, to November 20, 2020, on a longitudinal basis. Survey responses were categorized as before surgery (≤120 days), short term after surgery (<30 days; ST), and long term after surgery (≥30 days; LT). Negative binomial regression was used to estimate the association of select covariates with PROs. Results: Eighty-five patients with Graves' disease were included. The majority were female (83.5%); 47.1% were non-Hispanic white and 35.3% were non-Hispanic black. The median thyrotropin (TSH) value before surgery was 0.05, which increased to 0.82 in ST and 1.57 in LT. In bivariate analysis, the Total Symptom Burden Score, a composite of all patient-reported burden, significantly reduced shortly after surgery (before surgery mean of 56.88 vs. ST 39.60, p < 0.001), demonstrating improvement in PROs. Furthermore, both the Thyroid Symptoms Score, including patient-reported thermoregulation, palpitations, and dysphagia, and the Quality-of-Life Symptom Score improved in ST and LT (thyroid symptoms, before surgery 13.88 vs. ST 8.62 and LT 7.29; quality of life, before surgery 16.16 vs. ST 9.14 and LT 10.04, all p < 0.05). After multivariate adjustment, the patient-reported burden in the Thyroid Symptom Score and the Quality-of-Life Symptom Score exhibited reduction in ST (thyroid symptoms, rate ratio [RR] 0.55, confidence interval [CI]: 0.42-0.72; quality of life, RR 0.57, CI: 0.40-0.81) and LT (thyroid symptoms, RR 0.59, CI: 0.44-0.79; quality of Life, RR 0.43, CI: 0.28-0.65). Conclusions: Quality of life and thyroid-specific symptoms of Graves' patients improved significantly from their baseline before surgery to both shortly after and longer after surgery. This work can be used to guide clinicians and patients with Graves' disease on the expected outcomes following total thyroidectomy.

Both BRAF V600E mutation and older age (≥ 65 years) are associated with recurrent papillary thyroid cancer.

PURPOSE: This study was designed to examine the aggressive features of BRAF-positive papillary thyroid cancer (PTC) and association with age. METHODS: We compared the clinicopathologic parameters and BRAF V600E mutation status of 121 elderly (age ≥65 years) PTC patients who underwent thyroidectomy from January 2007 to December 2009 to a consecutive cohort of 98 younger (age <65 years) PTC patients. RESULTS: Younger and elderly PTC patients had similar incidences of BRAF-positive tumors (41% vs. 38%; p = 0.67). The elderly cohort was more likely to have smaller tumors (mean 1.6 vs. 2.1 cm; p = 0.001), present with advanced TNM stage (36% vs. 19%; p = 0.008), and have persistent/recurrent disease (10% vs. 1%; p = 0.006). BRAF-positive status was associated with PTC that were tall cell variant (p < 0.001), had extrathyroidal extension (p < 0.001), lymph node involvement (p = 0.008), advanced (III/IV) TNM stage (p < 0.001), and disease recurrence (p < 0.001). Except for lymph node involvement, the association between aggressive histology characteristics at presentation and BRAF-positive PTC also was observed within the age-defined cohorts. In short-term follow-up (mean, 18 months), persistent/recurrent PTC was much more likely to occur in patients who were both BRAF-positive and elderly (22%). CONCLUSIONS: BRAF mutations are equally present in younger and older patients. Aggressive histology characteristics at presentation are associated with BRAF-positive PTC, irrespective of age. However, the well-established association of BRAF with recurrence is limited to older (age ≥65 years) patients.

Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations.

Von Hippel-Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype-phenotype correlations but, unlike other familial syndromes such as MEN-2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow-up of 15.5 and 12.1 years, respectively (P = 0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P = 0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P = 0.04), as well as malignant (P < 0.01) and lethal (P = 0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P = 0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation-specific malignancy and expression patterns exist within the VHL type 2A subtype, and provides information that may help tailor the screening and management algorithms of affected members and those at risk.