BACKGROUND:TERT gene mutations play critical roles in tumor progression and have important implications in several solid tumors, including thyroid carcinoma. This study aimed to evaluate the association between TERT promoter mutations and histology and clinical features of thyroid carcinoma (TC). MATERIALS AND METHODS:We performed an up-to-date systematic review and a comprehensive meta-analysis. Systematic searches were made on MEDLINE (via Pubmed) databases using relevant keywords, and articles published until November 1st, 2024 were selected. A total of 54 studies and 17'021 samples are included in the meta-analysis. Relevant data for the meta-analysis was extracted, and for statistical analysis, chi-square calculation was used. RESULTS:Thyroid carcinomas with the highest frequency of TERT mutations are Anaplastic thyroid carcinoma (55.8 %) and Diffuse sclerosing variant of papillary thyroid carcinoma (60.4 %). No TERT mutations founds in Benign neoplasm, NIFTP and Medullary thyroid carcinoma. Mutations with the highest frequency is c.-124C>T (chr5:1295228 - C228T). TERT mutations are statistically correlated with Stage III&IV, presence of metastasis, overall survival, recurrence and radioiodine-refractory. CONCLUSION:TERT mutation plays a crucial role as a prognostic biomarker with tumor aggressiveness. Thus, in clinical practice, mutational status assessment of the TERT promoter should be considered for accurate prognostic stratification of TCs.

IntroductionNormocalcemic primary hyperparathyroidism (NHPT) is considered to be an early stage in the evolution of primary hyperparathyroidism (PHPT). To formulate a correct diagnosis, secondary hyperparathyroidism due to low calcium intake must be excluded. Whether dietary calcium intake might affect the clinical presentation of PHPT or NHPT has never been addressed consistently.ObjectiveTo describe patients with a diagnosis of NHPT or PHPT in relation to their calcium intake, through three standard validated questionnaires; to describe clinical, biochemical and radiological features of NHPT and PHPT patients compared to each other and to a control group.DesignCross-sectional study.SettingOutpatient, single academic medical center.Patients109 consecutive women recruited from February 2021 through April 2023. 54 patients with mild primary hyperparathyroidism (PHPT or NHPT) were age-matched with 55 unselected women undergoing bone density test screening due to recently diagnosed hormone-positive breast cancer. NHPT diagnosis was based on multiple determinations of both total and albumin-corrected serum calcium.InterventionsAdministration of all the following during routine endocrine consultation: a country-specific food-frequency questionnaire (LOC), the International Osteoporosis Foundation Calcium Calculator (IOF) and the National Osteoporosis Foundation calcium questionnaire (NOF).Main outcome measuresAny association between dietary calcium intake and clinical, radiological, or biochemical features.ResultsAll three questionnaires confirmed that NHPT patients had similar calcium intake as those with PHPT or controls. Biochemistries and bone turnover markers were similar between the two variants of hyperparathyroidism, except for serum calcium (sCa). NHPT patients had a significantly lower BMD and T-score at one-third distal radius compared to PHPT, while the prevalence of nephrolithiasis and clinical fractures were similar. Multivariate analysis investigating predictors of serum calcium showed that age, eGFR, calcium intake and 25(OH)D did not significantly affect serum calcium, while multivariate analysis investigating predictors of PTH (age, variant NHPT vs. PHPT, eGFR, calcium intake, 25(OH)D, cholecalciferol supplements) showed that calcium intake, variant and renal function, significantly influenced PTH levels.ConclusionsAll patients with primary hyperparathyroidism, particularly those with low dietary calcium intake, should be advised not to restrict dietary calcium to prevent further increase in PTH levels. Whether maintaining adequate calcium intake might positively impact bone density or biochemistries in patients refraining from surgery, should be addressed in longitudinal studies.

Thyroid cancer is the most prevalent endocrine malignancy. Distinct genetic alterations drive the development and progression of thyroid tumors of follicular cells with remarkable genotype–phenotype correlation. In most tumors of follicular cell origin, the primary molecular events are RAS or RAS-like (follicular-patterned tumors) and BRAF p.V600E or BRAF V600E-like (conventional papillary carcinomas) alterations. Progression of thyroid tumors to advanced and less-differentiated carcinomas requires additional oncogenic alterations, including TP53 and TERT promoter mutation, and aberrant PI3K–PTEN–AKT signaling. Understanding the genetic landscape of thyroid carcinoma of follicular cells is essential to optimize clinical management and to identify molecular targets to treat cases with aggressive disease refractory to standard radioactive iodine therapy. What follows is a comprehensive and updated outline of the main somatic genetic and molecular alterations in thyroid carcinoma of follicular cells.

CONTEXT:The risk of recurrence of papillary thyroid carcinoma (PTC) smaller than 1 cm (microPTC) is low. Predictors of disease persistence in microPTC are still unclear. OBJECTIVE:To compare the clinical and pathological characteristics of microPTCs with macrocarcinomas (PTC > 1 cm), identifying the predictors of biochemical and structural incomplete response 1 year after initial treatment in microPTC. METHODS:We included patients consecutively enrolled in the Italian Thyroid Cancer Observatory (NCT04031339), and selected patients with a histological diagnosis of PTC for whom complete pathological, clinical, treatment information, and results at the 1-year follow-up visits were available. RESULTS:Among 5038 patients in the cohort, 2345 (46.5%) had a microPTC. Patients with microPTCs had tumors with more indolent pathological features: only 3% of patients were classified as high risk according to the American Thyroid Association (ATA) risk stratification system for persistent or recurrent disease and 1% had distant metastases at diagnosis. MicroPTCs had a significantly better outcome: only 5% had a biochemical response and 2.3% a structural incomplete (SIR) response. Distant metastases at diagnosis were the best predictor of SIR in microPTCs (OR 5.13, 95% CI 1.11-23.73, P = .04). In a subgroup of 925 patients treated by total thyroidectomy and radioiodine treatment, the best predictor of SIR was the ATA high risk (OR 5.47, 95% CI 1.42-21.04, P = .01). CONCLUSION:Our study confirms the favorable initial outcome of microPTC in a large series. We demonstrate that the ATA risk classification is reliable in predicting biochemical and structural persistence in patients with microPTC. Distant metastases, although rare, remain the best predictor of structural persistence at 1-year follow-up. These findings underscore the importance of tailored management strategies based on comprehensive risk stratification, rather than solely on tumor size.

BACKGROUND:Total thyroidectomy for patients with sporadic medullary thyroid carcinoma is often recommended because of multifocality. The International Medullary Thyroid Carcinoma Grading System is established as a predictor of disease-specific outcomes. We aimed to study multifocality and its association with index tumor grade and somatic mutations. METHODS:A retrospective cohort analysis of 5 high-volume medullary thyroid carcinoma centers was performed between January 1, 1986, and January 1, 2018. Thyroidectomy specimens were evaluated for multifocality. Molecular profiling was assessed with RET germline testing and/or targeted exome sequencing of specimens with matched normal DNA. Outcomes evaluated were risk of local recurrence, distant recurrence, and survival within 15 years. RESULTS:Among 270 patients with nongermline medullary thyroid carcinoma, 207 (77%) were unifocal and 63 (23%) multifocal (P < .05). A similar proportion of patients were low-grade (unifocal: 75% vs multifocal: 79%; P = .45) although a significantly greater proportion of multifocal patients demonstrated C-cell hyperplasia (48% vs 9%; P < .001). Molecular profiling identified no differences among driver mutations. The median size of multifocal lesions was 0.60 cm (interquartile range: 0.3-1.0 cm) with 74% harboring multiple foci. The ratio of positive lymph nodes in dissected compartments was similar (multifocal: 0.37, interquartile range: 0-0.66 vs unifocal: 0.27, interquartile range: 0-0.43; P = .23). Local recurrence (P = .25) and overall survival (P = .31) were not statistically different between cohorts. CONCLUSION:Subcentimeter multifocality is common in sporadic medullary thyroid carcinoma. In this study cohort, no differences were observed in tumor grade, lymph node burden, overall survival, or somatic driver mutations compared with unifocal tumors. Multifocality in patients with sporadic medullary thyroid carcinoma is not associated with adverse overall survival.

Anaplastic thyroid cancer (ATC) is an aggressive and lethal malignancy with limited therapeutic options and poor prognosis. In recent years, the therapeutic arsenal of locally advanced or metastatic ATC has been expanded, with V-Raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen-activated protein kinase kinase-MAPKK (MEK) inhibitors for the subset of BRAF V600E-mutant ATC. For BRAF wild-type ATC and without other actionable alterations, the most promising strategy is certainly immune checkpoint inhibitors, which have shown activities both in monotherapy or in combination regimens. However, access to novel treatments is heterogeneous worldwide for ATC patients, and activity of immunotherapy as a single agent is limited. We report the case of a patient with locally advanced BRAF wild-type ATC who achieved a near-complete and durable response following a multimodal treatment approach combining chemotherapy (carboplatin and paclitaxel), immunotherapy (pembrolizumab), and external beam radiotherapy. Pembrolizumab monotherapy was continued as maintenance therapy, and disease control was maintained for over 1 year. This case highlights the potential efficacy of chemo-immunotherapy in BRAF wild-type ATC, especially when a rapid tumor reduction is required. It supports the use of immune checkpoint inhibitors combined with cytotoxic agents as a viable therapeutic option in this aggressive tumor subtype.

Purpose whole body scan (WBS) performed following diagnostic or therapeutic administration of I-131 is useful in patients with differentiated thyroid carcinoma. However, it can be falsely positive in various circumstances. We aimed to report a series of pitfalls in a clinical perspective. Methods A search in the database PubMed utilizing the following terms: “false radioiodine uptake” and “false positive iodine 131 scan” has been made in January 2023. Among the 346 studies screened, 230 were included in this review, with a total of 370 cases collected. Physiological uptakes were excluded. For each patient, sex, age, dose of I-131 administered, region and specific organ of uptake and cause of false uptake were evaluated. Results 370 cases of false radioiodine uptake were reported, 19.1% in the head-neck region, 34.2% in the chest, 14.8% in the abdomen, 20.8% in the pelvis, and 11.1% in the soft tissues and skeletal system. The origin of false radioiodine uptake was referred to non-tumoral diseases in 205/370 cases (55.1%), benign tumors in 108/370 cases (29.5%), malignant tumors in 25/370 cases (6.7%), and other causes in 32/370 cases (8.7%). Conclusions WBS is useful in the follow-up of patients with differentiated thyroid carcinoma, however it can be falsely positive in various circumstances. For this reason, it is critically important to correlate the scintigraphic result with patient’s medical history, serum thyroglobulin levels, additional imaging studies and cytologic and/or histologic result.

Thanks to the identification of crucial molecular pathways, the therapeutic landscape for advanced differentiated thyroid tumors (DTCs) has significantly improved during the last ten years. The therapeutic scenario has been greatly impacted by the discovery of mutually exclusive gene changes in the MAPK and PI3K/AKT pathways, such as RET or NTRK fusions and pathogenic mutations of the BRAF and RAS genes. Indeed, multi-kinase inhibitors and selective inhibitors have demonstrated outstanding efficacy for radioactive iodine-refractory (RAI-R) drug treatment, with overall response rates reaching up to 86%. Thus, for RAI-R DTCs, routine molecular testing for actionable gene alterations is now essential, for choosing the right therapy for the right patient.Additionally, tumor genotyping also allows to identify a subset of patients with worse prognosis disease, which may deserve a tailored clinical management. Thus, the right test should also include non-driver TERT, TP53, PIK3CA, and other mutations of aggressiveness, with the aim of a molecular-based risk stratification. Therefore, tumor genotyping should be considered in the diagnostic work-up of metastatic DTC patients or with highly aggressive histological features, in order to give the right drug for the right patient at the right time.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OBJECTIVE:Atypical parathyroid tumor (aPT) and parathyroid carcinoma (PC) are extremely rare parathyroid neoplasms, accounting together for <2% of all parathyroid tumors. They often present an overlapping clinical phenotype, sharing clinical, biochemical, and some histological features. They are distinguished only by the presence of local invasion, and lymph nodes or distant metastasis, which are all absent in aPTs. To date, only few studies have compared clinical presentation and features between aPTs and PCs. Our purpose was to conduct a retrospective study on a multicenter Italian database of aPT and PC patients. DESIGN AND METHODS:We comparatively analyzed main features of aPT (n = 57) and PC (n = 74) patients collected at 15 major endocrinology and endocrine surgery centers in Italy. RESULTS AND CONCLUSIONS:Atypical parathyroid tumors and PCs showed no significant differences in many clinical features and presented similar values of elevated parathyroid hormone and total serum calcium. Renal complications, namely nephrolithiasis and nephrocalcinosis, appeared to be more common in PC, with a significantly higher rate of renal colic, regardless of total serum calcium levels and 24-h calciuria. Parathyroid carcinomas showed significantly higher postoperative disease persistence and recurrence rates, presumably due to an uncomplete resection of the primary tumor in 23.5% of cases and/or presence of unremoved active metastasis, but they had similar disease-free mean time after surgery than aPT. To deepen the study of malignant parathyroid tumors, the institution of a novel Italian retro-prospective multicenter registry of aPTs and PCs is currently ongoing, and a dedicated PC European registry has been recently activated.

Abstract Backgrounds To report the long-term surgical outcomes and the impact on daily life activities of strabismus surgery in patients with Thyroid Associated Orbitopathy (TAO) with and without previous orbital decompression. Methods Patients who underwent strabismus surgery for TAO were retrospectively reviewed. The primary outcome was to evaluate the influence of orbital decompression on the outcomes of TAO related strabismus surgery. Surgical success was defined by the resolution of diplopia and a post-operative deviation < 10 prism diopters (PD). The secondary outcomes were the clinical features, surgical approaches, and impact on daily life activities. Results A total of 45 patients were included in the study. The decompression surgery group (DS) included 21 patients (46.7%), whereas the non-decompression surgery group (NDS) patients were 24 (53.3%). The mean follow-up time from the last strabismus surgery was 2,8 years (range 8–200 months). Successful surgical outcome was achieved in 57,1% of patients in the DS, and 75% of patients in the NDS (p = 0,226). DS patients required almost twice the number of surgical interventions for strabismus compared to the NDS (1,95 vs. 1,16 respectively, p = 0,006), a higher number of extraocular muscles recessed in the first surgery (2,67 vs. 1,08 respectively, p < 0.001), and a lower rate of unidirectional surgery compared to NDS (23% vs. 95%, p < 0,001). At the pre-operative assessment, 71.4% of DS patients had eso-hypotropia, while no patients had this type of strabismus in the NDS group (p < 0.001). On the other hand, the hypotropia rate was 79.2% in NDS patients and only 4.8% in DS patients (p < 0.001). Moreover, 21,8% of NDS patients used prism lenses in daily life activities, compared to 42.9% of patients that used prism lenses to reduce the impairment in their daily life activities (p = 0.016). Conclusions The results of our study showed that DS patients required almost twice the number of strabismus surgical procedures, a higher number of extraocular muscles recessed in the first surgery, and an increased need for prism lenses to correct the residual deviation compared to the NDS, but with similar long-term surgical outcomes.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aims Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi‐institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence‐free survival (RFS) in MTC. Methods and Results Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10‐fold cross‐validation was used to optimize the model's performance. To assess discrimination and calibration, the area‐under‐the‐curve (AUC) of a receiver operating characteristic (ROC) curve, concordance‐index ( C ‐index), and dissimilarity index ( D ‐index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C ‐index of 0.876, and a D ‐index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. Conclusions Using well‐established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/ .

Tumors of the endocrine glands are common. Knowledge of their molecular pathology has greatly advanced in the recent past. This review covers the main molecular alterations of tumors of the anterior pituitary, thyroid and parathyroid glands, adrenal cortex, and adrenal medulla and paraganglia. All endocrine gland tumors enjoy a robust correlation between genotype and phenotype. High-throughput molecular analysis demonstrates that endocrine gland tumors can be grouped into molecular groups that are relevant from both pathologic and clinical point of views. In this review, genetic alterations have been discussed and tabulated with respect to their molecular pathogenetic role and clinicopathologic implications, addressing the use of molecular biomarkers for the purpose of diagnosis and prognosis and predicting response to molecular therapy. Hereditary conditions that play a key role in determining predisposition to many types of endocrine tumors are also discussed.

Il carcinoma midollare della tiroide è un tumore a origine neuroendocrina derivato dalle cellule della cresta neurale. Nonostante sia raro, è gravato da tassi di mortalità più alti se confrontato con i carcinomi differenziati dalla tiroide. Dalla prima descrizione istologica (1959) sono trascorsi 61 anni per introdurre il concetto di “grado tumorale” in questo tipo di neoplasia, mutuandolo dai corrispettivi tumori neuroendocrini gastrointestinali. La nuova classificazione basata sul grado tumorale proposta dal Sistema Internazionale del grading del carcinoma midollare (IMTCGS) suddivide i tumori in basso e alto grado a seconda della conta mitotica, dei livelli di KI67, e della presenza/assenza di necrosi. Tale classificazione si è dimostrata superiore rispetto al sistema della American Joint Committee on Cancer (AJCC-TNM) nel predire sia la sopravvivenza globale sia quella correlata alla malattia, come anche i tassi di recidiva. Passeremo in rassegna la descrizione delle tre classificazioni del grading proposte recentemente.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Objectives Preoperative localization of pathological parathyroid glands with imaging is essential for focused unilateral neck exploration and minimally invasive techniques. Recently published studies suggested that contrast enhanced ultrasonography (CEUS) had high accuracy in the localization of hyperfunctioning parathyroid glands, with a general increase in the sensitivity as compared to conventional sonography. The purpose of this study was to determine the usefulness of CEUS in the localization of parathyroid lesions relating to surgical and histopathological data, in comparison to color Doppler ultrasound (CDUS), in the same series of patients. Methods Records of 142 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings. Results The overall sensitivity of CEUS was 77.6% compared with 74.6% for CDUS, although no significative differences were found (P = .516). Conversely, CDUS has shown higher sensitivity than CEUS in the group of patients with associated thyroid pathology but there was no statistical difference (P = .529). The sensitivity for detection of multiple adenomas was the same for both procedures. Conclusions We found no significative superior sensitivity of CEUS also in case of concomitant thyroid pathology and multiple glands disease.

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.