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Machine learning (ML) is an interdisciplinary sector in the subset of artificial intelligence (AI) that creates systems to set up logical connections using algorithms, and thus offers predictions for complex data analysis. In the present review, an up-to-date summary of the current state of the art regarding ML and AI implementation for thyroid nodule ultrasound characterization and cancer is provided, highlighting controversies over AI application as well as possible benefits of ML, such as, for example, training purposes. There is evidence that AI increases diagnostic accuracy and significantly limits inter-observer variability by using standardized mathematical algorithms. It could also be of aid in practice settings with limited sub-specialty expertise, offering a second opinion by means of radiomics and computer-assisted diagnosis. The introduction of AI represents a revolutionary event in thyroid nodule evaluation, but key issues for further implementation include integration with radiologist expertise, impact on workflow and efficiency, and performance monitoring.

In this study, we investigated the profile of microRNAs (miRNAs) contained in exosomes secreted in the serum of patients with papillary thyroid cancer (PTC). Exosome were isolated by adding ExoQuick Exosome Precipitation Solution. Dynamic light scattering (DLS) and western blotting analysis were used to ensure the quality of exosomes. The expression levels of miRNAs were investigated using custom-designed TaqMan Advanced miRNA Array Cards in the screening cohort and using specific TaqMan Advanced MicroRNA Assays in the validation cohort. We identified miR24-3p, miR146a-5p, miR181a-5p and miR382-5p with different expression levels in two different series of 56 and 58 PTC patients as compared with healthy controls. Significant differences in the expression of three PTC exosomal miRNAs, depending on the presence of lymph node metastasis, were detected in only one PTC series. When comparing the expression levels of some PTC-specific exosomal miRNAs with those of the same miRNAs circulating free of any encapsulation, we found a significant correlation for only miR24-3p, suggesting that only select miRNAs are secreted in exosomes. Our findings demonstrate that four miRNAs are differently secreted in the exosomes of PTC patients, whereas no conclusive results were found to characterize PTCs with lymph node metastasis, suggesting caution in the use of circulating exosomal miRNA expression levels as lymph node metastasis biomarkers. Further investigation into the mechanisms governing miRNA secretion in tumor cells are required.

Family history of thyroid cancer increases the risk of harboring thyroid malignancies that end up having extrathyroidal extension (ETE) and multifocality on histology, some authors suggest a more aggressive surgical approach. Their pre-operative identification could allow more conservative surgical procedures if none of these features are suspected. Our aim was to assess if neck ultrasonography could identify or exclude multifocality or ETE in these patients to tailor the extent of surgery. This retrospective study included patients with previous thyroid surgery, ≥1 first-grade relative with thyroid cancer, and who had undergone pre-surgical ultrasound. ETE was suspected in the case of thyroid border interruption or gross invasion of perithyroidal tissues. Multiple suspicious nodules were defined as suspicion of multifocal cancer. The cohort consisted of 45 patients (median age 49 years, 40 with thyroid cancer, 30 females). The positive predictive value of ultrasonography in predicting multifocality and ETE was 57.14% (25.25–84.03) and 41.67% (21.5–65.1%), respectively, while the negative predictive values were 63.2% (56.4–69.4%) and 72.7% (63.3–80.5%). Pre-operative ultrasound examination is unable to reliably identify or exclude multifocal disease or extrathyroidal extension. In patients scheduled for surgery and with a first-degree relative affected by DTC, a “negative” pre-operative US report does not exclude the potential finding of multifocality and ETE at final histopathology.

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory (ITCO) database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p=0.65), tumor size >2 cm (OR 1.45, p=0.34), aggressive PTC histology (OR 0.55, p=0.15), and age at diagnosis (OR 0.90, p=0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27, 95% CI, p=0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and non-treated patients (p=0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Ultrasound (US) is the first imaging modality for thyroid parenchyma evaluation. In the last decades, the role of ultrasound has been improved with the introduction of new US software, such as contrast-enhanced ultrasound (CEUS) and US-elastography (USE). USE is nowadays recognized as an essential part of the multiparametric ultrasound (MPUS) examination, in particular for the indeterminate thyroid nodule with possible fine-needle aspiration cytology (FNAC) number reduction; even if further and larger studies are needed to validate it. More controversial is the role of CEUS in thyroid evaluation, due to its high variability in sensitivity and specificity. Semi-automatic US systems based on the computer-aided diagnosis (CAD) system are producing interesting results, especially as an aid to less experienced operators. New knowledge on the molecular mechanisms involved in thyroid cancer is allowing practitioners to identify new genomic thyroid markers that could reduce the number of “diagnostic” thyroidectomies. We have therefore drawn up an updated representation of the current evidence in the literature for thyroid nodule multiparametric ultrasound (MPUS) evaluation with particular regard to USE, the US CAD system and CEUS.

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio >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 >1) and an arbitrary alternative definition (AP/T ratio >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 < 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.

Surgery-with or without postoperative radioiodine-is the standard of care for most patients with differentiated thyroid carcinoma (DTC). Thyroid hormone replacement therapy is the mainstay of long-term medical management. Patients treated with total thyroidectomy and some who undergo lobectomy alone require thyroid hormone therapy to restore euthyroidism with normal serum thyroid-stimulating hormone (TSH) levels. Because TSH acts as a growth factor for thyroid follicular cells (including those that are neoplastic), it can potentially affect the onset and/or progression of follicular-cell derived thyroid cancer. For this reason, some patients are placed on thyroid hormone therapy at doses that suppress secretion of TSH (suppression therapy). This mini-review looks at the potential benefits and risks of this practice in patients diagnosed with DTC. Aggressive TSH-suppressive therapy is of little or no benefit to the vast majority of patients with DTC. Practice guidelines, therefore, recommend a graded algorithm in which the potential benefits of suppression are weighed against the associated cardiovascular and skeletal risks. Large randomized controlled studies are needed to confirm the presumed oncological benefits of TSH-suppression and its causal role in adverse cardiac, skeletal, and quality of life effects and to assess the efficacy of TSH normalization in reversing or reducing these effects.

Objective The second version of The Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP. Design Systematic review and meta-analysis. Methods A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC. Results One-hundred fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14 and 3%, respectively. Conclusion This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14 and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment.

Congenital hypothyroidism (CH) is a neonatal endocrine disorder that might occur as itself or be associated to congenital extra-thyroidal defects. About 85% of affected subjects experience thyroid dysgenesis (TD), characterized by defect in thyroid gland development. In vivo experiments on null mice paved the way for the identification of genes involved thyroid morphogenesis and development, whose mutation has been strongly associated to TD. Most of them are thyroid-specific transcription factors expressed during early thyroid development. Despite the arduous effort in unraveling the genetics of TD in animal models, up to now these data have been discontinuously confirmed in humans and only 5% of TD have associated with known null mice-related mutations (mainly PAX8 and TSHR). Notwithstanding, the advance in genetic testing represented by the next-generation sequencing (NGS) approach is steadily increasing the list of genes whose highly penetrant mutation predisposes to TD. In this review we intend to outline the molecular bases of TD, summarizing the current knowledge on thyroid development in both mice and humans and delineating the genetic features of its monogenetic forms. We will also highlight current strategies to enhance the insight into the non-Mendelian mechanisms of abnormal thyroid development.

Context Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck. Objective To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy. Design Retrospective analysis of prospectively recorded data. Setting Academic center. Patients Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable ( Interventions Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes. Main Outcome Measures Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits. Results In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment. Conclusions Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels

The aim of the study was to describe the spontaneous TSH level variations and levothyroxine dose adjustments in athyreotic patients with differentiated thyroid cancer (DTC) in real-life practice. Patients with DTC were retrospectively evaluated at a tertiary referral center between October 2006 and November 2013. Hormone measurements (TSH and FT4 serum levels), L-T4 prescription information (dose per kg per day) and other medications were recorded at 1 month and 3, 12, 24, 36 and 48 months after primary treatment (surgery ± radioiodine therapy). The cohort was composed of 452 patients; about 20% of patients with stable levothyroxine dose have clinically meaningful spontaneous TSH variations (defined as ΔTSH > 2 mcUI/mL) at yearly follow-up visit. Furthermore, about 25% of athyreotic DTC patients with stable dose have a ΔTSH > 1.5 mcUI/mL and about 40% a ΔTSH > 1 mcUI/mL during each follow-up visit. We further investigated whether this TSH variation would lead to subsequent dose changes. About 19.9–37.7% of DTC patients on stable LT4 dose on the previous visit had their levothyroxine dose reduced, while 7.8–14.9% increased due to TSH variations. We further evaluated the decision to change the dose in relation with the age-specific TSH range. Up to 77.2% of patients had their dose adjusted due to TSH falling below the age-specific range. Spontaneous serum TSH variations determine levothyroxine replacement therapy in athyreotic patients with DTC, requiring multiple dose changes.

Purpose: Several studies have shown that different tumour types sharing a driver gene mutation do not respond uniformly to the same targeted agent. Our aim was to use an unbiased network-based approach to investigate this fundamental issue using BRAF mutant tumours and the BRAF inhibitor vemurafenib. Methods: We applied SWIM, a software able to identify putative regulatory (switch) genes involved in drastic changes to the cell phenotype, to gene expression profiles of different BRAF mutant cancers and their normal counterparts in order to identify the switch genes that could potentially explain the heterogeneity of these tumours' responses to vemurafenib. Results: We identified lung adenocarcinoma as the tumour with the highest number of switch genes (298) compared to its normal counterpart. By looking for switch genes encoding for kinases with homology sequences similar to known vemurafenib targets, we found that thyroid cancer and lung adenocarcinoma have a similar number of putative targetable switch gene kinases (5 and 6, respectively) whereas colorectal cancer has just one. Conclusions: We are persuaded that our network analysis may aid in the comprehension of molecular mechanisms underlying the different responses to vemurafenib in BRAF mutant tumours.

The SARS-CoV-2 pandemic is a worldwide public health emergency. Despite the beginning of a vaccination campaign, the search for new drugs to appropriately treat COVID-19 patients remains a priority. Drug repurposing represents a faster and cheaper method than de novo drug discovery. In this study, we examined three different network-based approaches to identify potentially repurposable drugs to treat COVID-19. We analyzed transcriptomic data from whole blood cells of patients with COVID-19 and 21 other related conditions, as compared with those of healthy subjects. In addition to conventionally used drugs (e.g., anticoagulants, antihistaminics, anti-TNFα antibodies, corticosteroids), unconventional candidate compounds, such as SCN5A inhibitors and drugs active in the central nervous system, were identified. Clinical judgment and validation through clinical trials are always mandatory before use of the identified drugs in a clinical setting., Graphical Abstract ga1

Follicular thyroid cancer (FTC) is the second most common histologic subtype of differentiated thyroid cancer behind papillary thyroid cancer (PTC). The rate of FTC diagnosis is declining over time due to changes in the diagnostic criteria and to environmental factors such as iodine sufficiency. The diagnosis is challenging because FTCs are distinguished from follicular thyroid adenomas (FTAs) solely by the presence of capsular and/or vascular invasion, neither of which can be assessed in cytology specimens. FTC spreads through blood vessels, and lymph node metastases are rarer (

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

Ultrasonography (US) is the most accurate tool for exploring cervical lymph nodes for persistent/recurrent lesions in patients with papillary thyroid cancers (PTCs). Certain features are highly informative (the sole presence of punctuate hyperechogenicity or a cystic appearance, which predicts PTC involvement with an accuracy of 100 %; visualization of the lymph node “fatty” hilum, which virtually excludes malignancy). Other findings, such as nonvisualization of the hilum or a round rather than oval shape, are considered diagnostically indeterminate because of their limited specificity. The suspicious node’s location, the patient’s estimated risk of recurrence, and serum Tg levels are important considerations as well. Confirmation of metastatic involvement is usually based on cytological assessment of a fine-needle aspirate, but even in experienced hands, cytology can yield false-negative results (6–8 % of cases), and up to 10 % of aspirates are inadequate for diagnosis. The diagnostic yield can be enhanced by immunometric assay of Tg levels and/or PCR-based assay of transcript levels for thyroid-specific genes (Tg, TSHR) in washout fluid from the needle used to collect the cytology aspirate. The former can accurately identify PTC lymph node metastases (sensitivity, 88–100 %; specificity, 69–100 %), even in the presence of circulating Tg antibodies. Thanks to the use of PCR amplification, the genetic approach can correctly identify metastases from PTCs, even when the washout fluid contains only a few cells, and its accuracy vs. histology is 100 %.

Radioactive iodine (RAI) remnant ablation (RRA) is not routinely performed after thyroidectomy for patients with low-to-intermediate American Thyroid Association (ATA) risk for recurrent papillary thyroid cancer (PTC). The specificity of serum thyroglobulin (Tg) assay positivity as a marker of persistent/recurrent disease may be lost in these cases since there is no way to distinguish Tg production by neoplastic tissue from that synthesized by the normal thyroid remnant. However, temporal trends in serum Tg levels can still be informative in these cases. In most cases, remnant Tg production drops below 0.2 ng/mL during the first year of follow-up after total thyroidectomy. In a small subset of patients, however, the decline plateaus above this cutoff level. If Tg levels remain stable and neck ultrasound (US) findings are negative during the follow-up, watchful waiting by performing periodic neck US examinations and Tg assays may be an appropriate approach.

Context Current guidelines recommend a selective use of radioiodine treatment (RAI) for papillary thyroid cancer (PTC). Objective This work aimed to determine how policy changes affect the use of RAI and the short-term outcomes of patients. Methods A retrospective analysis of longitudinal data was conducted in an academic referral center of patients with nonaggressive PTC variants; no extrathyroidal invasion or limited to soft tissues, no distant metastases, and 5 or fewer central-compartment cervical lymph node metastases. In cohort 1, standard treatments were total thyroidectomy and RAI (May 2005-June 2011); in cohort 2 decisions on RAI were deferred for approximately 12 months after surgery (July 2011-December 2018). Propensity score matching was used to adjust for sex, age, tumor size, lymph node status, and extrathyroidal extension. Intervention included immediate RAI or deferred choice. Main outcome measures were responses to initial treatment during 3 or more years of follow-up. Results In cohort 1, RAI was performed in 50 of 116 patients (51.7%), whereas in cohort 2, it was far less frequent: immediately in 10 of 156 (6.4%), and in 3 more patients after the first follow-up data. The frequencies of structural incomplete response were low (1%-3%), and there were no differences between the 2 cohorts at any follow-up visit. Cohort 2 patients had higher rates of “gray-zone responses” (biochemical incomplete or indeterminate response). Conclusion Selective use of RAI increases the rate of patients with “uncertain” status during early follow-up. The rate of structural incomplete responses remains low regardless of whether RAI is used immediately. Patients should be made aware of the advantages and drawbacks of omitting RAI.

Purpose To assess Strain Ratio (SRE) and Shear Wave Elastography (SWE) accuracy alone and with TIRADS classification, for the risk stratification of indeterminate thyroid nodules. Materials and methods 128 Patients with 128 indeterminate nodules candidates for thyroidectomy underwent preoperative staging neck ultrasound and were classified according to K-TIRADS score. After TIRADS evaluation, semi-quantitative (SRE) and quantitative (SWE expressed in kPa) elastosonography were performed and relative diagnostic performances, alone and in combination, were compared through ROC curves analysis. In order to maximize the SRE and SWE sensitivity and specificity, their cut-off values were calculated using the Liu test. Bonferroni test was used to evaluate statistically significant differences with a p value Results Sensitivity, specificity, PPV and NPV were, respectively, 71.4%, 82.4%, 62.5%, 87.5% for K-TIRADS baseline US, 85.7%, 94.1%, 85.7%, 94.1% for SRE and 57.1%, 79.4%, 53.3%, 81.8% for SWE (kPa expressed). SRE evaluation showed the best diagnostic accuracy compared to the SWE (kPa expressed) (p p > 0.05). The association of SRE with conventional ultrasound with K-TIRADS score increased sensitivity (92.9% vs 71.4%) but decreased the specificity than conventional US alone (76.5% vs 82.4%). Conclusion Strain Elastosonography can be associated with K-TIRADS US examination in the thyroid nodule characterization with indeterminate cytology; in fact, adding the SRE to K-TIRADS assessment significantly increases its sensitivity and negative predictive value. However, further multicenter studies on larger population are warranted.

Ultrasonographic risk-stratification systems (RSS), including various Thyroid Imaging Reporting and Data Systems (TIRADS), were proposed to improve reporting and reduce the number of fine-needle aspiration biopsies. However, age might be a confounder since some suspicious ultrasonographic features lack specificity in elderly patients. We aimed to investigate whether the diagnostic performance of the RSS varied between age groups. All patients consecutively referred for thyroid biopsy between November 1, 2015, and March 10, 2020, were included. The malignancy risk of each nodule was estimated according to five RSS: the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi guidelines, the American College of Radiology (ACR) TIRADS, the American Thyroid Association guidelines, the European TIRADS, and the Korean TIRADS. Overall, 818 nodules (57 malignant) were evaluated. The malignancy rate was higher in patients &le, 65 years (8.1%) than in patients &gt, 65 years (3.8%, p = 0.02). All RSS confirmed a significant discriminative performance in both age groups, with a negative predictive value of 100% in patients &gt, 65 years, although specificity was lower in older patients. The ACR TIRADS was the best performing in both age groups. RSS could avoid a sizable number of biopsies when applied as rule-out tests in elderly patients.

Background. Spontaneous serum TSH variations during levothyroxine replacement therapy and multiple dose changes in athyreotic patients seem to be frequent in clinical practice. Aim. To describe the rate and extent of spontaneous serum TSH variations in patients after total thyroidectomy for differentiated thyroid cancer (DTC) in real-life practice, and the number of resulting levothyroxine (LT4) dose adjustments. Methods. Data of DTC patients were prospectively collected at a single referral center between January 2005 and May 2019. TSH and fT4 serum levels, LT4 dose and formulation, and concomitant medications were recorded at 1, 3, and 12 months after primary treatment (surgery ± radioiodine therapy), and then yearly; the data were retrospectively evaluated for this study. Visit at one month was used to tailor LT4 dose and was not considered into the data analysis. Patients with structural evidence of disease or during pregnancy were excluded. Results. Data of 2883 evaluations (472 patients) were collected; at baseline, the median age was 49.7 years, 73.5% were females. The LT4 formulation administered at baseline were tablets (84.9%), liquid solution (11.4%), or soft-gel capsule (3.7%). Overall, in 27.5% of clinical evaluation with unchanged levothyroxine dose (341/1243), there were meaningful spontaneous TSH variations (defined as delta TSH > 1.5 mcUI/ml) at yearly follow-up visit. It is clinically significant: in 6.6% of visits, overt thyrotoxicosis was recorded. Furthermore, the treating clinicians decided to change the LT4 dose in 37.1% of cases. These figures were not significantly higher in the first years, and a rate above 25% persist even after ten years of follow-up. The median maintenance dose needed was 1.61 (interquartile range [IQR] 1.41-1.92) mcg/Kg/day for tablets, 1.54 (IQR 1.39-1.79) mcg/Kg/day for liquid solution, and 1.46 (IQR 1.23-1.71) mcg/Kg/day for soft-gel capsules. After correction for daily dose, there was no difference in the rate of TSH variations > 1.5 mcUI/ml, or in the absolute value of median delta of TSH between the three formulations. In 20.1% of patients, the LT4 formulation was changed during the follow-up: it was more common in patients with a known gastroenteric disease (OR 1.76, p=0.03). Conclusions. TSH spontaneous variations and dose adjustments are very common in patients after total thyroidectomy, even during long-term follow-up: wide variations happen in more than 1/4 of all visits, and dose changes are needed in more than 1/3 of all evaluations. We were more inclined to change LT4 formulation in patients with known interference in LT4 absorption: however, no difference in TSH variations was recorded between users of three different formulations, even if soft-gel capsules seem to have a lower maintenance dose.

Background. Management and follow-up of differentiated thyroid cancer (DTC) are guided by the likelihood of disease persistence or recurrence. The American Thyroid Association (ATA) practice guidelines provide a risk-estimation system based on data mainly derived by retrospective, single-center, and small cohorts. Aim. To validate the ATA risk-stratification system in predicting persistent structural disease. Methods. We analyzed data from the Italian Thyroid Cancer Observatory’s observational, web-based database, which prospectively enrolls newly diagnosed DTC patients in 40 Italian centers. For the present study we selected consecutive cases satisfying the inclusion criteria: 1) histological diagnosis of DTC, including papillary, follicular, and poorly differentiated tumors; 2) registration in the ITCO database between January 1, 2013 and April 23, 2019; 3) clinical evaluation between 6 and 18 month after primary treatment, including enough data to estimate the response to the initial treatment. Exclusion criteria were: histological diagnosis of NIFTP, medullary, or anaplastic thyroid cancer. The response to the initial treatment was categorized as excellent, biochemical incomplete, structural incomplete, or indeterminate based on imaging findings (neck ultrasound and other imaging studies, if performed), basal or stimulated serum thyroglobulin levels, and anti-Tg antibody levels. To model the response to treatment, we used a cumulative link model; given the hierarchical structure of the data, with patients nested within centers, we used a mixed-effect model, with a center-specific intercept summarizing unobserved center-specific characteristics. Results. Complete data about initial treatment and response to treatment after 6-18 months since initial treatment was available for 2071 patients. According to the ATA system, 1109 patients (53.6%) were classified as low-risk, 796 (38.4%) as intermediate, and 166 (8.0%) as high-risk. Excellent response was recorded in 1576 (76.1%) patients, indeterminate in 376 (18.2%), biochemical incomplete in 33 (1.6%), and structural incomplete in 86 (4.2%).The ATA risk stratification system is a significant predictor of response to treatment after 6-18 months: classification as intermediate- and high-risk increased the likelihood of a response worse than excellent (OR 1.68 [95% confidence intervals, CI 1.34-2.10] and 3.23 [95% CI 2.23-4.67], respectively), and a persistent structural disease (OR 4.67 [95% CI 2.59-8.43] and 16.48 [95% CI 7.87-34.5], respectively. In both analyses, the effect of the center (taking into account center-specific features) was negligible and not statistically significant. Conclusion. The 2015 ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC, also if applied in a real-world setting consisting of several different clinical sites.

Deciding whether patients with a cytologically indeterminate thyroid nodule should be referred for surgery or for active surveillance is an important challenge for clinicians. The aim of this study was to evaluate the performance of a novel dual-component molecular assay as an ancillary molecular method for resolving indeterminate thyroid nodule cytology. We selected 156 thyroid nodules from those that had undergone fine-needle aspiration processed by liquid-based cytology and surgical resection between June 2016 and December 2017. The sample set included 63 nodules cytologically classified as indeterminate, and 93 other nodules randomly selected from those with non-diagnostic, benign, suspicious, or malignant cytology. Nucleic acids from each nodule were subjected to next-generation sequencing analysis for mutation detection in 23 genes and to digital polymerase chain reaction (PCR) evaluation for miR-146b-5p expression levels. Used alone, mutation analysis in the indeterminate subset (cancer prevalence: 22.5%) displayed high sensitivity (89%) and NPV (96%). In contrast, the miR-146b-5p assay offered high specificity (93%) and PPV (93%). Combined use of both analyses improved panel performance by eliminating false-negative results. These preliminary data suggest that a dual-component molecular test can increase the diagnostic accuracy of thyroid cytology alone by reducing the number of nodules that will be classified as indeterminate and increasing those that can be reliably classified as benign. If these findings are confirmed, this test can be considered for use in clinical practice and is expected to reduce diagnostic surgery and health care costs, and to improve patient quality of life.

Background Ultrasound (US) risk stratification systems (RSSs) have been developed to reduce the number of unnecessary fine needle aspirations (FNAs) of thyroid nodules. These systems were designed primarily to identify papillary thyroid carcinomas, thus their performance on follicular thyroid carcinoma (FTC) is debatable. The present study was undertaken to investigate the accuracy of RSSs in selecting FTCs for FNA. Methods Patients with FTC who underwent US examinations between 2012 and 2018 in 2 institutions were selected. US images were reviewed retrospectively, and FTCs were reclassified according to the American Association of Clinical Endocrinologist/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME), American College of Radiology (ACR-TIRADS), 2015 American Thyroid Association, British Thyroid Association, European Thyroid Association, Korean Society of Thyroid Radiology and Korean Society of Radiology, and Thyroid Imaging Reporting and Data System (TIRADS). Risk class and indication for FNA were assessed. Results Forty-five FTCs from 45 consecutive patients were included in the study. The median tumor diameter was 32 mm (range, 11-100), and ovoid isoechoic nodule with or without lobulated margins was the most frequent presentation. When FTCs were classified according to RSSs, the most common categories were intermediate and high risk, though 1 case in 3 was not classifiable. FTCs were classified as high risk/high suspicion/malignant in 11% to 74% of cases, with a statistically significant difference among the systems. FNA was indicated in 69% to 100% of cases, with good agreement among AACE/ACE/AME, ACR-TIRADS, and TIRADS. Conclusion Current RSSs show high performance in selecting FTCs for FNA. This result is mainly due to the dimensional RSSs cutoffs indicating FNA. On the contrary, given the reported unsuspicious echo-structural presentation of FTC and the recognized limitation of cytological assessment to detect it, caution is advised when using US to manage cytologically indeterminate nodules.

A preoperative neck ultrasound (US) is recommended for all patients with suspected thyroid cancer, to identify features potentially changing surgical extent. The extrathyroidal extension (ETE) is considered an indication for total thyroidectomy, but there is limited consensus on its US definition, and the interobserver reliability is low. This study aimed to evaluate the predictive value of neck US for ETE before surgery and to estimate the diagnostic performance of different US findings, evaluated during real-time examinations. Patients referred to surgery between November 1, 2015, and May 31, 2019, for a suspicious thyroid cancer underwent a preoperative neck US, with systematic assessment for ETE. Three definitions were tested: very restrictive (capsular disruption with suspicious images of surrounding tissues invasion), restrictive (including also capsular abutment with evidence of capsular disruption), and nonrestrictive (capsular abutment is sufficient). Histopathology report of ETE involving at least soft tissues was considered positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The study cohort included 128 patients, with 102 (79.7%) confirmed malignancies, and 44 (43.1%) histological ETE. The nonrestrictive definition had good sensitivity (86.4%) but low specificity (29.8%), with an NPV of 80.6%; the restrictive definition had higher specificity (81%), while the very restrictive had specificity and PPV of 100%. A more extensive surgical approach should not be based on US suspicion of ETE alone, with the possible exception of gross invasion appearance. The absence of any sign of ETE, on the other hand, has a substantial negative predictive value.

Objective: Several thyroid imaging reporting and data systems (TIRADS) have been proposed to stratify the malignancy risk of thyroid nodule by ultrasound. The TIRADS by the European Thyroid Association, namely EU-TIRADS, was the last one to be published. Design: We conducted a meta-analysis to assess the prevalence of malignancy in each EU-TIRADS class and the performance of EU-TIRADS class 5 vs 2, 3 and 4 in detecting malignant lesions. Methods: Four databases were searched until December 2019. Original articles reporting the performance of EU-TIRADS and adopting histology as reference standard were included. The number of malignant nodules in each class and the number of nodules classified as true/false positive/negative were extracted. A random-effects model was used for pooling data. Results: Seven studies were included, evaluating 5672 thyroid nodules. The prevalence of malignancy in each EU-TIRADS class was 0.5% (95% CI: 0.0–1.3), 5.9% (95% CI: 2.6–9.2), 21.4% (95% CI: 11.1–31.7), and 76.1% (95% CI: 63.7–88.5). Sensitivity, specificity, PPV, NPV, LR+, LR− and DOR of EU-TIRADS class 5 were 83.5% (95% CI: 74.5–89.8), 84.3% (95% CI: 66.2–93.7), 76.1% (95% CI: 63.7–88.5), 85.4% (95% CI: 79.1–91.8), 4.9 (95% CI: 2.9–8.2), 0.2 (95% CI: 0.1–0.3), and 24.5 (95% CI: 11.7–51.0), respectively. A further improved performance was found after excluding two studies because of limited sample size and low prevalence of malignancy in class 5. Conclusions: A limited number of studies generally conducted using a retrospective design was found. Acknowledging this limitation, the performance of EU-TIRADS in stratifying the risk of thyroid nodules was high. Also, EU-TIRADS class 5 showed moderate evidence of detecting malignant lesions.

Over 50% of newly diagnosed thyroid nodules are either cytologically benign or presumed to be benign on the basis of low-suspicion sonographic findings. The strategies used for their long-term surveillance are based mainly on the estimated residual risk of malignancy calculated with various ultrasonographic classification systems (e.g., Thyroid Image Reporting and Data Systems [TIRADS]). We conducted a longitudinal study to evaluate the temporal stability of the initial risk estimates computed with five widely used systems and to determine whether risk class increases during follow-up are indeed predictive of malignancy.We re-analyzed data prospectively collected at a single academic referral center on 232 patients (age: 54.1 ± 13.7 years) with 432 asymptomatic, sonographically or cytologically benign thyroid nodules at baseline (T0) and 122 new nodules that were present five years later (T5). At both time points, the sonographically estimated risk of malignancy was calculated as recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi, the American College of Radiologists' TIRADS, the American Thyroid Association's 2015 practice guidelines, the European Thyroid Association's TIRADS (EU-TIRADS), and the TIRADS of the Korean Society of Thyroid Radiology (K-TIRADS).For 57 to 127 (13.2-29.4%) of the original nodules, depending on the system used, the estimated malignancy risk increased over the 5-year interval. Of the nodules whose baseline risk had not warranted cytological assessment, very few (6.3-8.3%) met the criteria for cytology at the 5-year evaluation. Biopsy was indicated for only 4 to 8 (3.3-6.6%) of the new nodules based on T5 risk estimates. Despite these changes, none of the 232 patients was ever diagnosed with a cancer.Ultrasound-based risk classes of presumably benign thyroid nodules remain fairly stable over time, and changes warranting biopsy are rare indeed. The appearance of new nodules is a frequent event, but very few (5%) are classified as high risk, and only the 3-7% meet the criteria for cytological assessment. Collectively, these findings support the view that patients with presumably benign thyroid nodules can be safely followed with less intensive protocols.

Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ − 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.

The incidence of papillary thyroid microcarcinoma (microPTC) has dramatically increased in the last decades. Most of these tumors remain small and clinically "silent", only small number progress. Although thyroid surgery used to be the only therapeutic approach, recent guidelines now consider active surveillance for low-risk microPTC. For this reason, more accurate risk stratification of microPTC is needed. The optimal management of low-risk microPTC through accurate risk stratification represents a major clinical issue.

CONTEXT: Nearly one-third of all thyroid cancers are ≤1 cm. OBJECTIVE: To determine diagnostic pathways for microcarcinomas vs larger cancers. DESIGN/SETTING/PARTICIPANTS: Patients from Georgia and Los Angeles Surveillance, Epidemiology, and End Results (SEER) registries with differentiated thyroid cancer diagnosed in 2014 or 2015 were surveyed. Survey data were linked to SEER data on tumor and treatment characteristics. Multivariable logistic regression analysis was performed. MAIN OUTCOME MEASURES: Method of nodule discovery; reason for thyroid surgery. RESULTS: Of patients who underwent surgery, 975 (38.2%) had cancers ≤1 cm, and 1588 cancers (61.8%) were >1 cm. The reported method of nodule discovery differed significantly between patients with cancers ≤1 cm and those with cancers >1 cm (P < 0.001). Cancer ≤1 cm was associated with nodule discovery on thyroid ultrasound (compared with other imaging, OR, 1.59; 95% CI, 1.21 to 2.10), older patient age (45 to 54 years vs ≤44, OR, 1.45; 95% CI, 1.16 to 1.82), and female sex (OR, 1.51; 95% CI, 1.22 to 1.87). Hispanic ethnicity (OR, 0.71; 95% CI, 0.57 to 0.89) and Asian race (OR, 0.67; 95% CI, 0.49 to 0.92) were negative correlates. Cancers ≤1 cm were associated with lower likelihood of surgery for a nodule suspicious or consistent with cancer (OR, 0.48; 95% CI, 0.40 to 0.57). CONCLUSION: Thyroid microcarcinomas are more likely to be detected by ultrasound and less likely to be associated with surgery scheduled for known thyroid cancer. Understanding diagnostic pathways allows for targeted interventions to decrease overdiagnosis and overtreatment.

Fournier's gangrene is a rare and severe complication reported in patients with cancer treated with antiangiogenic drugs, most frequently with bevacizumab. The present report describes the case of an 80-year-old man with radioactive iodine-refractory metastatic thyroid cancer treated with lenvatinib (an oral multikinase inhibitor with antiangiogenic properties) who developed Fournier's gangrene in the absence of other known risk factors. To the best of our knowledge, this is the first case described during treatment with lenvatinib. The condition was likely due to a perturbation of vascular endothelial cells of the skin due to the inhibition of VEGF/VEGFR signaling. Fournier's gangrene may be a class effect of antiangiogenic treatment that clinicians should be aware of, as early diagnosis and treatment are associated with an improved outcome.

Summary The main purpose of cancer screening programmes should not be to detect all cancers, but to discover potentially fatal or clinically relevant cancers. The US Preventive Services Task Force recommends against screening for thyroid cancer in the general, asymptomatic adult population, as such screening would result in harms that outweigh any potential benefits. This recommendation does not apply to patients with symptoms or to individuals at increased risk of thyroid cancer because of a history of exposure to ionising radiation (in childhood, as radioactive fallout, or in medical treatment as low-dose radiotherapy for benign conditions or high-dose radiation for malignancy), inherited genetic syndromes associated with thyroid cancer (eg, familial adenomatous polyposis), or one or more first-degree relatives with a history of thyroid cancer. We discuss the evidence for and against screening individuals who are at high risk, and consider the different screening tools available.

Italian cytology system for thyroid fine-needle aspiration (FNA) includes indeterminate lesions at low- (Tir 3A) and high-risk (Tir 3B). The present retrospective multicenter study was undertaken to compare the histological type of cancers and disease-free survival in these two groups. Eight institutions participated. Thyroid cancer patients diagnosed and followed-up after Tir 3A or Tir 3B were reviewed. Histological diagnosis was adopted as the gold standard. Patients were defined with cancer recurrence or no evidence of disease. Disease-free survival (DFS) was calculated. A non-parametric statistical analysis was used. DFS was estimated by Kaplan–Meier method and Hazard Ratio (HR) defined the slope of curves. Two hundred and nine patients (median DFS 24 months) were enrolled and a 6.3% of these recurred. Tir 3B group had higher age (p = 0.014), larger cancer size (p = 0.0002), shorter DFS (p = 0.003), higher number of aggressive cancers (p = 0.006), and relapse frequency double than Tir 3A. At survival curves analysis, Tir 3B group had HR of 2.37 with respect to Tir 3A. At Cox’s proportional hazard regression analysis histology was the only significant predictor of relapse. While patients with thyroid FNA of Tir 3B should be addressed to surgery due to high likelihood of more aggressive cancer, a diagnostic surgery could be avoided in patients with Tir 3A if concurrent unsuspicious clinical features are found.

Several studies have shown that different tumour types sharing a driver gene mutation do not respond uniformly to the same targeted agent. Our aim was to use an unbiased network-based approach to investigate this fundamental issue using BRAFWe applied SWIM, a software able to identify putative regulatory (switch) genes involved in drastic changes to the cell phenotype, to gene expression profiles of different BRAFWe identified lung adenocarcinoma as the tumour with the highest number of switch genes (298) compared to its normal counterpart. By looking for switch genes encoding for kinases with homology sequences similar to known vemurafenib targets, we found that thyroid cancer and lung adenocarcinoma have a similar number of putative targetable switch gene kinases (5 and 6, respectively) whereas colorectal cancer has just one.We are persuaded that our network analysis may aid in the comprehension of molecular mechanisms underlying the different responses to vemurafenib in BRAF

Objective The Italian reporting system for thyroid cytology classifies indeterminate lesions as TIR3A (low risk) or TIR3B (high risk) and is meant to provide practical guidance rather than a detailed consideration of morphological features. We aimed to assess which cytological features have the most diagnostic value and whether they are effective in classifying nodules as either TIR3A or TIR3B and in predicting histological outcomes. Methods Thyroid fine-needle aspirates from 111 indeterminate nodules were reviewed blinded to clinical information, TIR3A/TIR3B classification, and histology in order to assess which cytological features (pooled into artefacts, smear background, architectural and nuclear atypia, and oncocytes) differentiate TIR3A from TIR3B, and benign from malignant histological outcomes. Results Of the cytological features examined, those specific for TIR3B included high cellularity, nuclear atypia, oncocyte predominance and transgressing vessels. Features specific for TIR3A included artefacts, low cellularity and oncocyte sparseness. Other features, such as microfollicules/trabeculae, were non-specific. Due to the different distributions of these features, three TIR3B subgroups were identifiable: follicular lesions with oncocytic changes, pure follicular lesions, and follicular lesions with nuclear atypia, whereas no subgroups were identifiable in TIR3A. Nuclear atypia was a significant indicator of malignancy, whereas oncocyte predominance was not a reliable predictor of malignancy. High cellularity and microfollicules/trabeculae were not indicative of any histological outcome. Conclusions The majority of the assessed features were good predictors of histological outcomes. The TIR3A category included undefined nodules due to the absence of characterising features, whereas the TIR3B category included nodules with a greater number of distinguishing features.

An ever-increasing population of patients with papillary thyroid cancer is engaging with health care systems around the world. Numerous questions about optimal management have arisen that challenge conventional paradigms. This is particularly the case for patients with low-risk disease, who comprise most new patients. At the same time, new therapies for patients with advanced disease are also being introduced, which may have the potential to prolong life. This review discusses selected controversial issues in adult papillary thyroid cancer management at both ends of the disease spectrum. These topics include: (i) the role of active surveillance for small papillary cancers; (ii) the extent of surgery in low-risk disease (lobectomy vs total thyroidectomy); (iii) the role of postoperative remnant ablation with radioiodine; (iv) optimal follow-up strategies in patients, especially those who have only undergone lobectomy; and (v) new therapies for advanced disease. Although our current management is hampered by the lack of large randomized controlled trials, we are fortunate that data from ongoing trials will be available within the next few years. This information should provide additional evidence that will decrease morbidity in low-risk patients and improve outcomes in those with distant metastatic disease.