Life expectancy and likelihood of surgery in multiple endocrine neoplasia type 1: AFCE and GTE cohort study.

BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.

Pancreatoduodenectomy for Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: An AFCE (Association Francophone de Chirurgie Endocrinienne) and GTE (Groupe d'étude des Tumeurs Endocrines) Study.

AIM: To assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs). BACKGROUND: The use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense. METHODS: Thirty-one MEN1 patients from the Groupe d'étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed. RESULTS: Indication for surgery was: Zollinger-Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0-433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13-110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8-98.3] and ten-year overall survival was 89.1% [CI 69.6-96.4]. After a mean follow-up of 151 months (range 0-433), the biochemical cure rate for MEN-1 related gastrinomas was 61%. CONCLUSION: In MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.

One-Year Postoperative Mortality in MEN1 Patients Operated on Gastric and Duodenopancreatic Neuroendocrine Tumors: An AFCE and GTE Cohort Study.

IMPORTANCE: In MEN1 patients with gastric and duodenopancreatic neuroendocrine tumors (GPD-NET), surgery aims to control secretions or to prevent metastatic spread, but after GPD-NET resection, postoperative mortality may be related to the surgery itself or to other associated MEN1 lesions with their own uncontrolled secretions or metastatic behavior. OBJECTIVE: To analyze the causes of death within 1 year following a GPD-NET resection in MEN1 patients. DESIGN: An observational study collecting data from the Groupe d'étude des Tumeurs Endocrines (GTE) database. The analysis considered the time between surgery and death (early deaths [<1 month after surgery] versus delayed deaths [beyond 1 month after surgery]) and the period (before 1990 vs after 1990). Causes of death were classified as related to GDP surgery, related to surgery for other MEN1 lesions or not related to MEN1 causes. SETTING: GTE database which includes 1220 MEN1 patients and 441 GPD-NET resections. PARTICIPANTS: Four hundred and forty-one GPD-NET resections. MAIN OUTCOME MEASURES: The primary end point was postoperative mortality within 1 year after surgery. RESULTS: Twenty-four patients met the inclusion criteria (2%). Median age at death was 50.5 years. Sixteen deaths occurred in the 30-day postoperative period (76%). Among the 8 delayed deaths, 3 occurred as a result of medical complications between 30 and 90 postoperative days. After 1990, mean age at death increased from 48 to 58 years (p = 0.09), deaths related to uncontrolled acid secretion disappeared (p < 0.001) and deaths related to associated MEN1 lesions increased from 8 to 54% (p = 0.16). CONCLUSION: Surgery and uncontrolled secretions remain the two main causes of death in MEN1 patients operated for a GPD-NET tumor. Improving the prognosis of these patients requires a strict evaluation of the secretory syndrome and MEN1 aggressiveness before GDP surgery.

Laparoscopic adrenalectomy by transabdominal lateral approach: 20 years of experience.

BACKGROUND: Laparoscopic adrenalectomy (LA) has become the standard technique for most indications. The aim of this study was to determine the predictive factors of intra- and postoperative complications in order to inform the orientation of patient to a surgeon with more experience in adrenal surgery. METHODS: From January 1994 to December 2013, 520 consecutive patients benefited from LA at Huriez Hospital, Lille, France. Each complication was graded according to the Dindo-Clavien-grade scale. The predictive factors of complications were determined by logistic regression. RESULTS: Fifty-two surgeons under the supervision of 5 senior surgeons (individual experience >30 LA) participated. Postoperative complications with a grade of ≥2 occurred in 52 (10 %) patients (29 (5.6 %) medical, 19 (3.6 %) surgical, and 4 (0.8 %) mixed complications) leading to 12 (2.3 %) reoperations. There was no postoperative death. Intraoperative complication happened in 81 (15.6 %) patients responsible for conversion to open adrenalectomy (OA) [odds ratio (OR) 13.9, CI 95 % 4.74-40.77, p < 0.001]. History of upper mesocolic or retroperitoneal surgery was predictive of intraoperative complication (OR 2.02, 1.05-3.91, p = 0.036). Lesion diameter ≥45 mm was predictive of intraoperative complication (OR 1.94, 1.19-3.15, p = 0.008), conversion to OA (OR 7.46, 2.18-25.47, p = 0.001), and adrenal capsular breach (OR 4.416, 1.628-11.983, p = 0.004). Conversion to OA was the main predictive factor of postoperative complications (OR 5.42, 1.83-16.01, p = 0.002). Under adequate supervision, the surgeon's individual experience and initial adrenal disease were not considered predictive of complications. CONCLUSION: Lesion diameter over 45 mm is the determinant parameter for guidance of patients to surgeons with more extensive experience.

Hereditary hyperparathyroidism--a consensus report of the European Society of Endocrine Surgeons (ESES).

BACKGROUND: Hereditary hyperparathyroidism has been reported to occur in 5-10 % of cases of primary hyperparathyroidism in the context of multiple endocrine neoplasia (MEN) types 1, 2A and 4; hyperparathyroidism-jaw tumour (HPT-JT); familial isolated hyperparathyroidism (FIHPT); familial hypocalciuric hypercalcaemia (FHH); neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant moderate hyperparathyroidism (ADMH). This paper aims to review the controversies in the main genetic, clinical and pathological features and surgical management of hereditary hyperparathyroidism. METHODS: A peer review literature analysis on hereditary hyperparathyroidism was carried out and analyzed in an evidence-based perspective. Results were discussed at the 2015 Workshop of the European Society of Endocrine Surgeons devoted to hyperparathyroidism due to multiple gland disease. RESULTS: Literature reports scarcity of prospective randomized studies; thus, a low level of evidence may be achieved. CONCLUSIONS: Hereditary hyperparathyroidism typically presents at an earlier age than the sporadic variants. Gene penetrance and expressivity varies. Parathyroid multiple gland involvement is common, but in some variants, it may occur metachronously often with long disease-free intervals, simulating a single-gland involvement. Bilateral neck exploration with subtotal parathyroidectomy or total parathyroidectomy + autotransplantation should be performed, especially in MEN 1, in order to decrease the persistent and recurrent hyperparathyroidism rates; in some variants (MEN 2A, HPT-JT), limited parathyroidectomy can achieve long-term normocalcemia. In FHH, surgery is contraindicated; in NSHPT, urgent total parathyroidectomy is required. In FIHPT, MEN 4 and ADMH, a tailored case-specific approach is recommended.

Long-term survival after adrenalectomy for stage I/II adrenocortical carcinoma (ACC): a retrospective comparative cohort study of laparoscopic versus open approach.

BACKGROUND: Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparoscopic approach has also been increasingly accepted for adrenal metastases but remains controversial for adrenocortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalectomy (OA) in the treatment of stage I and II ACC. METHODS: This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hospital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival. RESULTS: Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (p < 0.02). After a similar follow-up (66 ± 52 for LA and 51 ± 43 months for OA), Kaplan-Meier estimates of disease-specific survival and disease-free survival were identical in both groups (p = 0.65, p = 0.96, respectively). CONCLUSIONS: LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC ≤ 10 cm ACC. Our results suggest that LA can be safely proposed to patients with potentially malignant adrenal lesions smaller than 10 cm and without evidence of extra-adrenal extension.

Poorly differentiated thyroid carcinomas: application of the Turin proposal provides prognostic results similar to those from the assessment of high-grade features.

AIMS: To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). This was done using a series of 82 thyroid carcinomas of follicular origin. RESULTS: The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high-grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (≥ 4%) was an independent factor and predictor of cause-specific survival. CONCLUSION: With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up.

Complete pathological response following chemotherapy and radiotherapy in two cases of advanced anaplastic thyroid carcinoma.

Introduction: Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer with a bleak prognosis. Favorable outcomes are rare but help decipher molecular pathophysiology, investigate prognosis factors, and discover new therapeutic targets. Case presentation: Two patients were diagnosed with locally advanced nonresectable ATC, one with metastatic extension. Each patient received chemotherapy and radiotherapy, allowing thyroid surgical resection. In both cases, the pathological examination was consistent with complete response with no viable tumor cells. After follow-ups of 48 and 70 months, both patients remain disease-free. Molecular explorations on thyroid biopsies revealed microsatellite instability (MSI) and alterations on mismatch repair-gene complex, also PTEN and ATM variants in both cases. Both also presented with non-classical immune infiltrate composed of equal parts T CD4+ lymphocytes and macrophages. Conclusion: We report two cases of patients cured from advanced ATC and for the first time provide genetic and immunological explorations in this setting. It seems with these two cases that MSI-ATCs may indicate a better prognosis. Our study hypothesizes different responsible mechanisms including increased sensitivity to chemoradiotherapy and/or immune tumor infiltrate modulation.

Renal origin and size are independent predictors of survival after surgery for adrenal metastasis.

BACKGROUND: The adrenal gland is a frequent site of dissemination for certain types of tumors. Aggressive treatment remains controversial. The benefit of adrenalectomy has been observed, but the ultimate role remains to be elucidated. MATERIALS AND METHODS: We conducted a retrospective study analyzing the records of all patients with adrenal metastases submitted to adrenalectomy (open or laparoscopic) at our institution from 1981 to 2010. Baseline characteristics, operative outcomes, and survival were analyzed; predictive factors were also studied by multivariate analysis. RESULTS: A total of 65 patients were included with a median age of 60 years. Primary tumor sites were renal (35%), pulmonary (23%), melanoma (7%), colon (2%), liver (1%), and others. Mean metastasis size was 7 ± 4.2 cm with a mean interval to metastasis diagnosis of 39 months. Laparoscopic approach was done in 50% of cases. Postoperative morbidity was present in 9%, and 2 early deaths were observed. Median overall survival was 48 months and 45% at 5 years. Univariate and multivariate analyses showed better prognosis for renal metastases (p = 0.007 and 0.009) and those with size <5 cm (p = 0.011 and 0.031). Also in univariate analysis: synchronous (p = 0.02), symptomatic (p = 0.04), and laparoscopically operated (p = 0.033) metastasis showed higher survival rates. Metastasis from pulmonary tumors had the worst prognosis. CONCLUSIONS: Adrenalectomy should be considered in patients with adrenal metastasis from renal carcinoma, as well as in those with small secondary lesions from other type of tumor with a controlled primary disease. The clear benefit of adrenalectomy remains to be documented in pulmonary carcinoma metastasis.

Ectopic hormone-secreting pheochromocytoma: a francophone observational study.

BACKGROUND: Ectopic hormone-secreting pheochromocytomas are rare; only case reports exist in the literature. This condition has been linked with increased malignancy, familial syndromes, and ACTH secretion. We wanted to test these hypotheses and shed light on the nature of ectopic hormone-secreting pheochromocytomas. METHODS: This is a multicenter (francophone) observational study. Inclusion was based upon abnormal preoperative hormone tests in patients with pheochromocytoma that normalized after removal of the tumor. Where possible, immunohistochemistry was performed to confirm that ectopic secretion came from the tumor. RESULTS: Sixteen cases were found: nine female and seven male patients. Median age was 50.5 (range 31-89) years. Most presented with hypertension, diabetes, or cushingoid features. Ten patients had specific symptoms from the ectopic hormone secretion. Two had a familial syndrome. Of eight patients with excess cortisol secretion, three died as a result of the tumor resection: two had pheochromocytomas >15 cm and their associated cortisol hypersecretion complicated their postoperative course. The other died from a torn subhepatic vein. The 13 survivors did not develop any evidence of malignancy during follow-up (median 50 months). Symptoms from the ectopic secretion resolved after removal of the tumor. Immunohistochemistry was performed and was positive in eight tumors: five ACTH, three calcitonins, and one VIP. CONCLUSIONS: Most pheochromocytomas with ectopic secretion are neither malignant nor familial. Most ectopic hormone-secreting pheochromocytoma cause hypercortisolemia. Patients with a pheochromocytoma should be worked up for ectopic hormones, because removal of the pheochromocytoma resolves those symptoms. Associated cortisol secretion needs careful attention.

Adrenocortical carcinoma: which surgical approach?

INTRODUCTION: There are no randomised studies comparing open and laparoscopic approaches foradrenalectomy in patients with adrenal cortical carcinoma. METHODS: There is evidence of postoperative benefit for the patients undergoing laparoscopic adrenalectomy compared to open adrenalectomy (level B). RESULTS: Results from comparison of oncological outcomes in ACC between open and laparoscopic approaches are equivocal: increasedrisk of local recurrence and peritoneal carcinomatosis by the laparoscopic route (level D), and identical results between the two approaches in terms of survival, recurrence and peritoneal carcinomatosis (level C). CONCLUSION: An open approach is recommended in case of local invasion, with a view to achieving an R0 resection (level D). Laparoscopic resection of ACC/potentially malignant tumours, which includes removal of surrounding periadrenal fat and results in an R0 resection without tumour capsule rupture, may be performed for preoperative and intraoperative stage 1-2 ACC and tumours with a diameter < 10 cm (level C).

Outcome of operation in patients with adrenocortical cancer invading the inferior vena cava--a European Society of Endocrine Surgeons (ESES) survey.

BACKGROUND: Most patients with adrenocortical cancer (ACC) continue to present with advanced disease. Invasion into the inferior vena cava (IVC) defines stage III disease and the management of such patients raises additional difficulties. METHOD: A multicentre survey was organized by emailing a standardized proforma to members of the European Society of Endocrine Surgery (ESES). Anonymised retrospective clinical data were collected. RESULTS: Replies were received from 18 centres in nine countries. ACC with IVC invasion was encountered in 38 patients (18F:20M, age 15-84 years, median 54 years). There were 16 nonfunctioning tumours and 22 functioning tumours predominantly right-sided (26R:12L) and measuring 18-255 mm (median 115 mm). Fourteen patients had metastatic disease at presentation. Tumour thrombus extended in the prehepatic IVC (n = 21), subdiaphragmatic IVC (n = 6) or into the SVC/right atrium (n = 3). Open adrenalectomy was associated with resection of surrounding viscera in 24 patients (nephrectomy n = 16, liver resection n = 14, splenectomy n = 3, Whipple procedure n = 2). IVC was controlled locally (n = 27), at suprahepatic levels (n = 6) or necessitated cardiac bypass (n = 5). Complete resection (R0, n = 20) was achieved in the majority of patients, with a minority having microscopic persistent disease (R1, n = 7) or macroscopic residual disease (R2, n = 4). Perioperative 30-day mortality was 13% (n = 5). Postoperative Mitotane was used in 23 patients and chemotherapy in eight patients. Twenty-five patients died 2-61 months after their operation (median 5 months). Currently, 13 patients are alive at 2-58 months (median 16 months) with known metastatic disease (n = 7) or with no signs of distant disease (n = 6). CONCLUSION: This dataset is limited by the lack of a denominator as it remains unknown how many other patients with ACC presenting with IVC invasion did not undergo surgery. The relatively low perioperative mortality and the long disease-free survival achieved by some patients should encourage surgeons with adequate experience to offer surgical treatment to patients presenting with advanced adrenocortical cancers.

Quantitative dual isotope 123iodine/99mTc-MIBI scintigraphy: A new approach to rule out malignancy in thyroid nodules.

BACKGROUND: The aim of this study was to evaluate the role of dual isotope 123Iodine/99mTc-MIBI thyroid scintigraphy (IMS) in discriminating between malignant and benign lesions in indeterminate nodules using quantitative analysis methods. METHODS: Thirty-five consecutive patients with thyroid nodules of indeterminate or non-diagnostic cytology and cold on 123Iodine scintigraphy (10 Bethesda I, 24 Bethesda III-IV, 1 in which cytology was impossible) underwent IMS between 2017 and 2019 with uptake quantification at two time points ahead of thyroidectomy: early and late. Images were analyzed by two blinded physicians. RESULTS: Twelve nodules were malignant and 23 benign on histopathology. Mean uptake values were lower in benign than in malignant nodules at both time points: early, 8.7±4.1 versus 12.9±3.5 (P=0.005); and late, 5.3±2.7 versus 7.7±1.1 (P=0.008). Interobserver reproducibility was excellent. The intraclass correlation coefficient was 0.86 in benign and 0.92 in malignant lesions for early uptake result (ER) and 0.94 and 0.85 respectively for late uptake result (LR). The optimal LR cut-off  to exclude a diagnosis of malignancy was set at 5.9 . The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off were, respectively, 100%, 65.2%, 60%, 100% and 77.1%. CONCLUSION: Despite some study limitations, quantitative analysis of 99mTc-MIBI thyroid scintigraphy had a good reproducibility, which could help to rule out malignancy in non-diagnostic or indeterminate thyroid nodules and thereby reducing the number of patients undergoing unnecessary surgery when LR is below 5.9.

Varied Recurrent Laryngeal Nerve Course Is Associated with Increased Risk of Nerve Dysfunction During Thyroidectomy: Results of the Surgical Anatomy of the Recurrent Laryngeal Nerve in Thyroid Surgery Study, an International Multicenter Prospective Anatomic and Electrophysiologic Study of 1000 Monitored Nerves at Risk from the International Neural Monitoring Study Group.

Background: The recurrent laryngeal nerve (RLN) can be injured during thyroid surgery, which can negatively affect a patient's quality of life. The impact of intraoperative anatomic variations of the RLN on nerve injury remains unclear. Objectives of this study were to (1) better understand the detailed surgical anatomic variability of the RLN with a worldwide perspective; (2) establish potential correlates between intraoperative RLN anatomy and electrophysiologic responses; and (3) use the information to minimize complications and assure accurate and safe intraoperative neuromonitoring (IONM). Methods: A large international registry database study with prospectively collected data was conducted through the International Neural Monitoring Study Group (INMSG) evaluating 1000 RLNs at risk during thyroid surgery using a specially designed online data repository. Monitored thyroid surgeries following standardized IONM guidelines were included. Cases with bulky lymphadenopathy, IONM failure, and failed RLN visualization were excluded. Systematic evaluation of the surgical anatomy of the RLN was performed using the International RLN Anatomic Classification System. In cases of loss of signal (LOS), the mechanism of neural injury was identified, and functional evaluation of the vocal cord was performed. Results: A total of 1000 nerves at risk (NARs) were evaluated from 574 patients undergoing thyroid surgery at 17 centers from 12 countries and 5 continents. A higher than expected percentage of nerves followed an abnormal intraoperative trajectory (23%). LOS was identified in 3.5% of NARs, with 34% of LOS nerves following an abnormal intraoperative trajectory. LOS was more likely in cases of abnormal nerve trajectory, fixed splayed or entrapped nerves (including at the ligament of Berry), extensive neural dissection, cases of cancer invasion, or when lateral lymph node dissection was needed. Traction injury was found to be the most common form of RLN injury and to be less recoverable than previous reports. Conclusions: Multicenter international studies enrolling diverse patient populations can help reshape our understanding of surgical anatomy during thyroid surgery. There can be significant variability in the anatomic and intraoperative characteristics of the RLN, which can impact the risk of neural injury.

Is thymectomy worthwhile in central lymph node dissection for differentiated thyroid cancer?

BACKGROUND: Clinical guidelines edited in 2006 by the American Thyroid Association (ATA) and stated in the European Thyroid Association Consensus (ETA) recommend routine central lymph node dissection (level VI neck dissection) in addition to thyroidectomy for the surgical treatment of differentiated thyroid cancer. This central dissection increases the incidence of postoperative hypocalcemia, which is related to the resection or devascularization of the inferior parathyroids together with bilateral thymectomy. Some authors perform unilateral thymectomy in order to minimize this complication. Our aim was to study the benefit/risk (incidence of thymic lymph node metastases versus postoperative hypocalcemia) of both procedures. METHODS: We retrospectively reviewed the records of 138 patients who underwent total thyroidectomy with central neck lymph node dissection for differentiated thyroid cancer between 2004 and 2007. Bilateral thymectomy was performed in 45 patients (group 1, 15 males and 30 females) and unilateral thymectomy was performed in 93 patients (group 2, 27 males and 66 females). Forty-two papillary and 3 medullary cancers were found in group 1, and 75 papillary, 2 follicular, and 17 medullary cancers were found in group 2. The presence of thymic metastases at pathology and the occurrence of postoperative hypocalcemia were reviewed. RESULTS: Two cases of papillary thymic metastases were found in group 1. These were lymph node micrometastases localized in the ipsilateral side of the primary tumor in both cases. Transient hypocalcemia was significantly more frequent (P < 0.001) in group 1 than in group 2: 16 patients (35.5%) versus 10 (10.7%). There was one case of permanent hypocalcemia in group 1 after the follow-up period. CONCLUSIONS: Bilateral thymectomy risk outweighs any likely carcinologic benefit. We do not recommend routine bilateral thymectomy during central neck dissection for differentiated thyroid cancer.

Multicenter study of 19 aortopulmonary window parathyroid tumors: the challenge of embryologic origin.

BACKGROUND: Ectopic abnormal parathyroid glands are relatively common in the superior mediastinum but are rarely situated in the aortopulmonary window (APW). The embryological origin of these abnormal parathyroid glands is controversial. The purpose of this investigation was to investigate the embryological origin and the surgical management of abnormal parathyroid glands situated in the APW. METHODS: The databases of patients operated on for primary, secondary, and tertiary hyperparathyroidism at eight European medical centers with a special interest in endocrine surgery were reviewed to identify those with APW adenomas. Demographic features, localization procedures, and perioperative and pathology findings were documented. The embryological origin was determined based on the number and position of identified parathyroid glands. RESULTS: Nineteen (0.24%) APW parathyroid tumors were identified in 7,869 patients who underwent an operation for hyperparathyroidism (HPT) and 181 patients (2.3%) with mediastinal abnormal parathyroid glands. Ten patients had primary, eight had secondary, and one had tertiary HPT. Sixteen patients had undergone previous unsuccessful cervical exploration. In three patients, an APW adenoma was suspected by preoperative localization studies and was cured at the initial operation. Sixteen patients had persistent HPT of whom 15 were reoperated, resulting in 6 failures. Evaluation of 17 patients who had bilateral neck exploration allowed us to determine the most probable origin of the APW parathyroid tumors: 12 were supernumerary, 4 appeared to originate from a superior, and 1 from an inferior gland. CONCLUSIONS: Abnormal parathyroid glands situated in the APW are rare and usually identified after an unsuccessful cervical exploration. Preoperative imaging of the mediastinum and neck are essential. The origin of these ectopically situated tumors is probably, as suggested by our data, from a supernumerary fifth parathyroid gland or from abnormal migration of a superior parathyroid gland during the embryologic development.

25-hydroxy vitamin D deficiency causes parathyroid incidentalomas.

PURPOSE: 25-OH D3 (D3) deficiency causes secondary hyperparathyroidism. Asymmetric gland hypertrophy may also lead to unnecessary parathyroid gland resection by mistaking these glands for parathyroid incidentalomas. We tested the hypothesis that D3 deficiency causes parathyroid gland hypertrophy. METHOD: This is a prospective study of 100 consecutive patients undergoing total thyroidectomy. Pre-operative D3 measurement was made at first presentation and on the day after surgery. During thyroidectomy, the parathyroid glands were searched for and measured. Using an ellipsoid volume calculator, the gland volume was calculated. This was correlated with D3 and other possible confounding factors. RESULTS: Normal parathyroid volume is 25.1 mm(3). Parathyroid gland size correlated with D3 levels, p < 0.001. There is a greater asymmetry in gland volume in those patients with the lowest levels of D3 (Spearman's rank correlation coefficient r = -0.51). There was a significant difference in individual gland volume between D3 levels >30 ng/ml and those <30 ng/ml. However, there was no difference in mean gland volume between these groups. There was no difference in correlation according to pathology or thyroid specimen weight. CONCLUSION: There is a significant difference in both individual gland volume and variation in parathyroid gland volume according to D3 levels. Patients with a D3 level <30 ng/ml have a more asymmetrical hyperplasia corresponding with parathyroid incidentalomas. D3 levels should be measured pre-operatively in all patients undergoing total thyroidectomy to avoid unnecessary parathyroid resection.

Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B.

OBJECTIVE: We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband's brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. DESIGN AND METHODS: Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. RESULTS: A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband's brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. CONCLUSION: In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines).

BACKGROUND: Thymic neuroendocrine tumors (Th-NET) present a poor prognosis for patients with multiple endocrine neoplasia type 1 (MEN1). The purpose of this article was to study the clinical, biological, and pathological features of Th-NET in a large cohort of patients with MEN1. METHODS: The 761-patient MEN1 cohort from the GTE registry was used (Groupe des Tumeurs Endocrines). RESULTS: The actuarial probability of occurrence was 2.6% (range, 1.3-5.5%) at aged 40 years. All, except one, Th-NET patients were men. Four patients had no other associated lesions. The youngest patient was aged 16 years. Mean age at the time of diagnosis was 42.7 (range, 16.1-67.5) years. The 10-year probability of survival was 36.1% (range, 11.5-62%). Seven patients (33%) belonged to clustered MEN1 families. The spectrum of associated lesions in patients with Th-NET was not statistically different from the spectrum of the remainder of the cohort. Various endocrine markers were high, but none were sensitive or specific enough to be useful for Th-NET detection. CT-scan and MRI were always positive at the time of diagnosis. No particular mutation was found to be associated with Th-NET. Five cases underwent prophylactic thymectomy without success. CONCLUSIONS: Several end points may be helpful for future guidelines: (1) earlier detection of Th-NET in MEN1 patients is required; (2) screening of both sexes is necessary; (3) a prospective study comparing MRI vs. CT scan in yearly screening for Th-NET is needed; (4) a reinforced screening program must be established for patients who belong to clustered families; and (5) thymectomies must be performed in specialized centers.