Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.

Context: Medullary thyroid cancer (MTC) is a rare disease. Objective: The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis. Design Setting and Patients: This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included. Main Outcome Measures: The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed. Results: The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC. Conclusion: Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC.

ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: a prospective randomized trial.

BACKGROUND: Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. TRIAL DESIGN AND METHODS: Prospective randomized open multicenter phase III trial including patients with 11-40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/- 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. DISCUSSION (POTENTIAL IMPLICATIONS): If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. TRIAL REGISTRATION: NCT03570021. June 26,2018.

Dual-Time-Point 18F-Fluorocholine PET/CT Improves Characterization of Thyroid Nodules in Patients Referred for Primary Hyperparathyroidism: A Proof of Concept Study.

PURPOSE: Thyroid nodules frequently coexist with primary hyperparathyroidism (pHPT). Because of the increasing use of 18F-fluorocholine (18F-FCH) PET/CT in patients with pHPT, evaluation of its clinical utility for thyroid nodules characterization in this population is of paramount importance. Herein, we investigate the value of dual-point 18F-FCH PET/CT in the diagnosis of thyroid cancer in patients referred for pHPT imaging who have thyroid nodules. PATIENTS AND METHODS: All pHPT patients who underwent a dual-time point 18F-FCH PET/CT (at 5 and 60 minutes postinjection) between July 2019 and December 2020 were analyzed. Only those with a thyroid nodule greater than 10-mm and pathological analysis (criterion standard) were included. Nodule-to-thyroid SUVmax ratio was calculated at the 2 study points, as well as the 18F-FCH washout index (WO%). RESULTS: Twenty-seven patients (32 nodules) were included in this study. The final diagnoses were as follows: 27 benign nodules including 2 NIFTPs (noninvasive follicular thyroid neoplasm with papillary-like nuclear features) and 5 cancers of follicular origin. Early uptake ratio was significantly higher in malignant lesions than in benign nodules (P = 0.0008). Thyroid cancers were also characterized by a marked 18F-FCH washout index (WO% benign vs cancer: 2.9% ± 4.1% vs 45.5% ± 13.4%, P = 0.0001). Using a WO% threshold of 22.1%, 25/27 benign nodules and 5/5 malignant lesions were accurately classified (sensitivity of 100%, specificity of 92.6%, positive predictive value of 71.4%, and negative predictive value of 100%). The false-positive findings were related to the 2 NIFTPs that share similarities with thyroid cancer. CONCLUSIONS: Our preliminary results suggest to perform a dual-time-point PET/CT acquisition protocol in pHPT patients with uncharacterized centimeter thyroid nodules. However, the real impact of these promising results should be assessed by prospective studies on a larger cohort of patients.

Prognostic Factors and Survival Score for Patients With Anaplastic Thyroid Carcinoma: A Retrospective Study from a Regional Registry.

BACKGROUND/AIM: Anaplastic thyroid carcinoma (ATC) is the least common but most lethal of thyroid cancer, despite various therapeutic options, with limited efficacy. In order to help therapeutic decision-making, the purpose of this study was to develop a new prognostic score providing survival estimates in patients with ATC. PATIENTS AND METHODS: Based on a multivariate analysis of 149 retrospectively analyzed patients diagnosed with ATC from 1968 to 2017 at a referral center, a propensity score was developed. A model was generated providing survival probability at 6 months and median overall survival estimates. RESULTS: The median survival was 96 days. The overall survival rate was 35% at 6 months, 20% at 1 year and 13% at 2 years. Stepwise Cox regression revealed that the most appropriate death prediction model included metastatic spread, tumor size and age class as explanatory variables. This model made it possible to define three categories of patients with different survival profiles. CONCLUSION: Distant metastasis, age and primary tumor size are strong independent factors that affect prognosis in patients with ATC. Using these significant pretreatment factors, we developed a score to predict survival in these patients with poor prognosis.

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

BACKGROUND: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

Long-term progression of non-invasive follicular thyroid neoplasm with papillary-like nuclear features: A single-center retrospective study of the French Marne-Ardennes thyroid cancer registry.

CONTEXT: Non-invasive forms of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) were reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment. A few studies showed neck lymphadenopathy at diagnosis, or even distant metastasis in patients with NIFTP. OBJECTIVE: Our aim was to report the frequency, clinical features and long-term progression of histologically confirmed NIFTP, using data from the French Marne-Ardennes thyroid cancer registry, and to compare findings against FVPTC. METHODS: This was a retrospective study on data for follicular variant of PTC (FVPTC) diagnosed between 1975 and 2015 obtained from the specialized Marne-Ardennes thyroid cancer registry. Pathology reports were used to select appropriate cases from a large series, and FVPTC specimens were reviewed by endocrine pathologists. Strict diagnostic criteria were used for reclassification as NIFTP. RESULTS: In total, 115 cases were reviewed histologically out of 383 cases of FVPTC. Sixty-five met all criteria for NIFTP and were consequently reclassified. Incidence of NIFTP was 16.9% of cases of FVPTC. Fifty patients were women (76.9%); median age was 47 years. Mean NIFTP size was 2.6 cm. There were no significant differences in age, gender or tumor size between NIFTP and FVPTC. Fifty patients underwent total thyroidectomy and 15 lobectomy. There were no lymph node metastases at diagnosis, and none of the patients (N=17) who underwent central and/or lateral neck dissection had positive findings on microscopic examination. 46 patients (70.8%) received radioiodine (RAI). Patients were followed up for 1.9-27.3 years (median 14.6 years) after initial treatment. All patients remained in complete remission during follow-up. CONCLUSION: Consistently with previous studies, our results showed the indolent course of NIFTP and that risk of recurrence after complete resection is very low (zero in our cohort), even when size is ≥4cm and in absence of adjuvant RAI treatment. Prospective studies are needed to confirm those results.

Added value of 18F-fluorocholine positron emission tomography-computed tomography in presurgical localization of hyperfunctioning parathyroid glands after dual tracer subtraction scintigraphy failure: A retrospective study of 47 patients.

Hyperparathyroidism is a common endocrine disorder. The precise localization of causal parathyroid gland is crucial to guide surgical treatment. Several studies report the added value of 18F-fluorocholine (FCH) positron emission tomography-computed tomography (PET/CT) as second line imaging but rely on suboptimal first-line imaging using 99mTc-sestaMIBI dual phase scintigraphy. The aim of this study is to evaluate the percentage of successful parathyroid localization with FCH PET/CT after failure of a more sensitive first-line detection protocol associating neck ultrasonography and 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy.We included retrospectively 47 patients who underwent a FCH PET/CT as second line imaging for biologically proven primary hyperparathyroidism from November 2016 to October 2018 in Godinot Institute (Reims, France). 99mTc-Pertechnetate/99mTc-sestaMIBI dual tracer subtraction scintigraphy and neck ultrasonography were used as first-line imaging and failed to localize the causal parathyroid lesion in all cases.FCH PET/CT demonstrated at least 1 parathyroid target lesion in 29 patients (62%). 21/29 patients underwent surgery. Target lesions corresponded histologically to hyperfunctioning parathyroid glands for all 21 patients and surgery was followed by hyperparathyroidism biological resolution. Calcium serum levels were associated to FCH PET/CT positivity (P = .002) and a trend toward significance was seen for Parathyroid hormone (PTH) levels (P = .09).FCH PET/CT is a promising tool in second-line parathyroid imaging. Large prospective studies and cost-effectiveness analyses are needed to precise its role.

Micropapillary carcinoma: Description and rise in incidence in the French Marne-Ardennes thyroid cancer registry.

CONTEXT: Yearly incidence of thyroid cancer has nearly tripled in the past four decades, due to improvements in and better use of diagnostic procedures, enabling detection of smaller tumors, and notably micropapillary carcinoma (MPC: ≤10 mm). OBJECTIVES: The aim of our study was to confirm increasing incidence, to describe the characteristics and circumstances of discovery, and to examine the reasons for this rise in incidence of MPCs, based on the French Marne-Ardennes registry for 1975-2014. DESIGN: This was a retrospective observational cohort study. RESULTS: Two thousand six hundred and seventy-one patients with thyroid cancer were included for the period 1975-2014, with 966 (36.2%) MPCs. The percentage increased from 18.9% for 1975-1984 to 45.1% for 2005-2014. Standardized incidence per 100,000 patient-years increased from 0.86 for 1975-1984 to 6.20 for 2005-2014. Incidence increase was higher in women (ranging from 1.15 to 8.91) than in men (from 0.20 to 2.54). Incidence increased more in ≥50 year-olds (from 0.41 to 4.21) than in <50 year-olds (from 0.45 to 1.99). Most MPCs (84.6%) were discovered incidentally on histology, and were mainly unifocal (79.4%). Incidental MPCs were smaller, affected older patients and were less multifocal than those suspected before surgery. MPCs were associated with excellent survival and low morbidity, with <1.9% progression. CONCLUSION: The present study confirmed the large rise in incidence of MPCs reported elsewhere. Most MPCs were discovered incidentally on histological examination in the context of surgery for benign pathology. Changes in access to health care and in physicians' and pathologists' practices are likely explanations for our findings.

Acute pyelonephritis revealing an intraprostatic obstructive megaureter in an adult: A rare finding.

INTRODUCTION: Duplicated renal collecting system is one of the most common congenital upper urinary tract abnormalities. Duplex system with ectopic obstructive megaureter in the prostatic urethra is rare and exceptionally revealed in adulthood. PRESENTATION OF CASE: We present a rare case of a 72-year-old man without any previous history of urinary symptoms, admitted through the emergency department for altered general condition associated with fever for several days. Investigations have identified left complete duplex system and intraprostatic obstructive megaureter manifesting as acute pyelonephritis. The evolution of acute pyelonephritis was favorable under urine drainage by percutaneous nephrostomy tube and antibiotherapy. Given the multiple comorbidities of the patient, radical surgical treatment by left upper pole nephrectomy was ruled out and we opted for an iterative change of percutaneous nephrostomy tube. DISCUSSION: We briefly review the pathophysiology, diagnosis and therapeutic aspects. CONCLUSION: Early diagnosis and treatment of complicated duplex system is important. Urologists should keep this anomaly in mind.