Studio osservazionale prospettico sull’outcome clinico dei pazienti affetti da carcinoma della tiroide

Aim: To identify clinical and molecular prognostic factors in differentiated thyroid cancer (DTC) Methods: A web based longitudinal database of newly diagnosed DTC was settled down. The risk of recurrence and the response to treatment were classified according to the American Thyroid Association (ATA) guidelines. Circulating miR analysis of sera collected before surgery and about 1 months and 1-2 years after surgery was performed with TaqMan MicroRNA Assay. Results: 2730 patients had a follow-up ≥1 year. The ATA risk of recurrence was low in 1386 (50.8%), intermediate in 1168 (42.8%) and high in 176 (6.4%). The response to treatment was excellent in 1675 (61.3%), biochemical incomplete in 63 (2.3%), structural incomplete in 70 (2.6%), and indeterminate in 922 (33.8%). A significantly higher rate of structural disease was found in intermediate (2.7%, Odds ratio 4.85, 95% confidence interval 2.18 - 12.23, p<0.01) and high risk (17.1% Odds ratio 35.21, 95% confidence interval 15.41 - 90.66, p<0.01) patients compared with low risk patients (0.6%). Of the 829 patients that had a follow up of ≥3 years, only 3 (0.6%) intermediate risk patients experienced relapse. Serum samples of 44 patients with papillary thyroid cancer (PTC) were available for miR profiling. After a screening analysis, miR-146a-5p and miR-221-3p were selected for validation because of superior accuracy in PTC identification from healthy controls and benign thyroid nodules. The trend over time of miR-146a-5p and miR-221-3p was decreasing in patients with disease remission and increasing in patients with structural disease. In 3 cases miR profile was more informative than the serum thyroglobulin. Conclusion: The ATA risk stratification is an effective clinical prognostic tool for structural disease prediction in DTC. One third of the patients has an indeterminate response to treatment due to low detectable serum markers (thyroglobulin or anti thyroglobulin antibodies). miR profile may represents a promising alternative marker of disease status for these patients

ENDOCRINE TUMOURS: Imaging in the follow up of differentiated thyroid cancer: current evidence and future perspectives for a risk-adapted approach

The clinical and epidemiological profiles of differentiated thyroid cancers (DTCs) have changed in the last three decades. Today's DTCs are more likely to be small, localized, asymptomatic papillary forms. Current practice is though moving towards more conservative approaches (e.g. lobectomy instead of total thyroidectomy, selective use of radioiodine). This evolution has been paralleled and partly driven by rapid technological advances in the field of diagnostic imaging. The challenge of contemporary DTCs follow up is to tailor a risk-of-recurrence-based management, taking into account the dynamic nature of these risks, which evolve over time, spontaneously and in response to treatments. This review provides a closer look at the evolving evidence-based views on the use and utility of imaging technology in the post-treatment staging and the short- and long-term surveillance of patients with DTCs. The studies considered range from cervical US with Doppler flow analysis to an expanding palette of increasingly sophisticated second-line studies (cross-sectional, functional, combined-modality approaches), which can be used to detect disease that has spread beyond the neck and, in some cases, shed light on its probable outcome. 

Recent advances in managing differentiated thyroid cancer

The main clinical challenge in the management of thyroid cancer is to avoid over-treatment and over-diagnosis in patients with lower-risk disease while promptly identifying those patients with more advanced or high-risk disease requiring aggressive treatment. In recent years, novel clinical and molecular data have emerged, allowing the development of new staging systems, predictive and prognostic tools, and treatment approaches. There has been a notable shift toward more conservative management of low- and intermediate-risk patients, characterized by less extensive surgery, more selective use of radioisotopes (for both diagnostic and therapeutic purposes), and less intensive follow-up. Furthermore, the histologic classification; tumor, node, and metastasis (TNM) staging; and American Thyroid Association risk stratification systems have been refined, and this has increased the number of patients in the low- and intermediate-risk categories. There is now a need for new, prospective data to clarify how these changing practices will impact long-term outcomes of patients with thyroid cancer, and new follow-up strategies and biomarkers are still under investigation. On the other hand, patients with more advanced or high-risk disease have a broader portfolio of options in terms of treatments and therapeutic agents, including multitarget tyrosine kinase inhibitors, more selective BRAF or MEK inhibitors, combination therapies, and immunotherapy

Interobserver agreement of various thyroid imaging reporting and data systems

Ultrasonography is the best available tool for the initial work-up of thyroid nodules. Substantial interobserver variability has been documented in the recognition and reporting of some of the lesion characteristics. A number of classification systems have been developed to estimate the likelihood of malignancy: several of them have been endorsed by scientific societies, but their reproducibility has yet to be assessed. We evaluated the interobserver variability of the AACE/ACE/AME, ACR, ATA, EU-TIRADS, and K-TIRADS classification systems and the interobserver concordance in the indication to FNA biopsy. Two raters independently evaluated 1055 ultrasound images of thyroid nodules identified in 265 patients at multiple time points, in two separate sets (501 and 554 images). After the first set of nodules, a joint reading was performed to reach a consensus in the feature definitions. The interobserver agreement (Krippendorff alpha) in the first set of nodules was 0.47, 0.49, 0.49, 0.61, and 0.53, for AACE/ACE/AME, ACR, ATA, EU-TIRADS, and K-TIRADS systems, respectively. The agreement for the indication to biopsy was substantial to near-perfect, being 0.73, 0.61, 0.75, 0.68, and 0.82, respectively (Cohen's kappa). For all systems, agreement on the nodules of the second set increased. Despite the wide variability in the description of single ultrasonographic features, the classification systems may improve the interobserver agreement, that further ameliorates after a specific training. When selecting nodules to be submitted to FNA biopsy, that is main purpose of these classifications, the interobserver agreement is substantial to almost perfect

Is thyroid nodule location associated with malignancy risk?

PURPOSE: Nodules located in the upper pole of the thyroid may carry a greater risk for malignancy than those in the lower pole. We conducted a study to analyze the risk of malignancy of nodules depending on location. METHODS: The records of patients undergoing thyroid-nodule fine-needle aspiration cytology (FNAC) at an academic thyroid cancer unit were prospectively collected. The nodules were considered benign in cases of a benign histology or cytology report, and malignant in cases of malignant histology. Pathological findings were analyzed based on the anatomical location of the nodules, which were also scored according to five ultrasonographic classification systems. RESULTS: Between November 1, 2015 and May 30, 2018, 832 nodules underwent FNAC, of which 557 had a definitive diagnosis. The prevalence of malignancy was not significantly different in the isthmus, right, or left lobe. Among the 227 nodules that had a precise longitudinal location noted (from 219 patients [155 females], aged 56.2±14.0 years), malignancy was more frequent in the middle lobe (13.2%; odds ratio [OR], 9.74; 95% confidence interval [CI], 1.95 to 48.59). This figure was confirmed in multivariate analyses that took into account nodule composition and the Thyroid Imaging, Reporting, and Data System (TIRADS) classification. Using the American College of Radiologists TIRADS, the upper pole location also demonstrated a slightly significant association with malignancy (OR, 6.92; 95% CI, 1.02 to 46.90; P=0.047). CONCLUSION: The risk of thyroid malignancy was found to be significantly higher for mid-lobar nodules. This observation was confirmed when suspicious ultrasonographic features were included in a multivariate model, suggesting that the longitudinal location in the lobe may be a risk factor independently of ultrasonographic appearance

Risk stratification of neck lesions detected sonographically during the follow-up of differentiated thyroid cancer

Context: The European Thyroid Association (ETA) has classified post-treatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence. Objective: To assess this classification's ability to predict the growth and persistence of such lesions during active post-treatment surveillance of patients with differentiated thyroid cancer (DTC). Design: Retrospective, observational study Setting: Thyroid cancer center, large Italian teaching hospital. Patients: Center referrals (2005–2014) were reviewed and patients selected with pathologically confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on ≥2 consecutive post-treatment neck sonograms; subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with ≥1 lesion classified as ‘suspicious’) and group I (‘indeterminate’ lesions only). We recorded baseline and follow-up clinical data through 30 June 2015. Main Outcomes: Patients with growth (> 3 mm, largest diameter) of ≥1 lesion during follow-up, patients with ≥1 persistent lesion at the final visit. Results: The cohort included 58 (9%) of the 637 DTC cases screened. A total of 113 lesions were followed (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 years), group I had significantly lower rates than group S of lesion growth (8% vs. 36%, p=0.01) and persistence (64% vs. 97%, p=0.014). Median time to scan normalization: 2.9 years. Conclusions: The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify PTC patients eligible for more relaxed follow-up

Non‐Marked Hypoechogenic Nodules : Multicenter Study on the Thyroid Malignancy Risk Stratification and Accuracy Based on TIRADS Systems Comparison

Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Background and Objectives: The aim of the study was to evaluate the predictive value of the ultrasound criterion “non‐marked hypoechogenicity” for malignancy and to determine whether classification of these nodules as TIRADS 3 could improve the overall accuracy of consequently adjusted M‐TIRADS score. Materials and Methods: A total of 767 patients with 795 thyroid nodules were subject to ultrasonography examination and ultrasound‐guided fine needle aspiration biopsy. Nodules were classified by Kwak TIRADS and modified (M‐TIRADS) categories 4A, 4B, and 5 according to number of suspicious US features (marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, taller‐than‐wide shape, metastatic lymph nodes). Non‐marked hypoechoic nodules were classified as TIRADS 3. Results: Thyroid nodules were classified as TIRADS 2, 3, 4A, 4B, and 5 in 14.5, 57.5, 14.2, 8.1, and 5.7%, respectively. Only histopathologic results (125 nodules underwent surgery) and highly specific cytology results (Bethesda II, VI) were accepted as a standard of reference, forming a sub‐cohort of 562/795 nodules (70.7%). Malignancy was found in 7.7%. Overall, M‐TIRADS showed sensitivity/specificity of 93.02/81.31%, and for PPV/NPV, these were 29.2/99.29%, respectively (OR—18.62). Irregular margins showed the highest sensitivity and specificity (75.68/93.74%, respectively). In TIRADS 3 category, 37.2% nodules were isoechoic, 6.6% hyperechoic, and 52.2% hypoechoic (there was no difference of malignancy risk in hypoechoic nodules between M‐TIRADS and Kwak systems—0.9 vs. 0.8, respectively). Accuracy of M‐TIRADS classification in this cohort was 78.26% vs. 48.11% for Kwak. Conclusions: The non‐marked hypoechoic nodule pattern correlated with low risk of malignancy; classification of these nodules as TIRADS 3 significantly improved the predictive value and overall accuracy of the proposed M‐TIRADS scoring with malignancy risk increase in TIRADS 4 categories by 20%; and no significant alteration of malignancy risk in TIRADS 3 could contribute to reducing overdiagnosis, obviating the need for FNA.publishersversionPeer reviewe

Taller-than-wide shape: a new definition improves the specificity of TIRADS systems

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio &gt;1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. Objective: The aim of this study was to estimate the impact of this definition on diagnostic performance. Methods: We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio &gt;1) and an arbitrary alternative definition (AP/T ratio &gt;1.2). Results: The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p &lt; 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Conclusions: Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker's specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance

Advances in functional imaging of differentiated thyroid cancer

Abstract: The present review provides a description of recent advances in the field of functional imaging that takes advantage of the functional characteristics of thyroid neoplastic cells (such as radioiodine uptake and FDG uptake) and theragnostic approach of differentiated thyroid cancer (DTC). Physical and biological characteristics of available radiopharmaceuticals and their use with state-of-the-art technologies for diagnosis, treatment, and follow-up of DTC patients are depicted. Radioactive iodine is used mostly with a therapeutic intent, while PET/CT with 18F-FDG emerges as a useful tool in the diagnostic management and complements the use of radioactive iodine. Beyond 18F-FDG PET/CT, other tracers including 124I, 18F-TFB and 68Ga-PSMA, and new methods such as PET/MR, might offer new opportunities in selecting patients with DTC for specific imaging modalities or treatments

A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency

Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis. There was no evidence of gene amplification. Expression analysis found an increase of RET transcript in p.Cys630=;p.Cys634Arg patient compared with that found in 7 MTCs harboring p.Cys634 mutations. Minigene expression assays demonstrated that the presence of the synonymous RET mutation was sufficient to explain the increased RET mRNA level. In silico analyses and RNA immunoprecipitation experiments showed that the p.Cys630 = variant created new exonic splicing enhancer motifs that enhanced SRp55 recruitment to the mutant allele, leading to more efficient maturation of its pre-mRNA and an increased abundance of mature mRNA encoding a constitutively active RET receptor. These findings document a novel mechanism by which synonymous mutations can contribute to cancer progression