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Livia Lamartina, Désirée Deandreis, Cosimo Durante and Sebastiano Filetti

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 toward 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.

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Massimo Bongiovanni, William C Faquin, Luca Giovanella, Cosimo Durante, Peter Kopp and Pierpaolo Trimboli


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.


Systematic review and meta-analysis.


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.


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.


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.

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Cosimo Durante, Giovanni Tallini, Efisio Puxeddu, Marialuisa Sponziello, Sonia Moretti, Claudia Ligorio, Antonio Cavaliere, Kerry J Rhoden, Antonella Verrienti, Marianna Maranghi, Laura Giacomelli, Diego Russo and Sebastiano Filetti


Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear.


The aim of our study was to investigate the impact of BRAF V600E on proangiogenic gene expression and microvascular features of PTCs.


mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFR β or PDGFRB) were measured with real-time PCR in BRAF V600E (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF V600E cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF V600E mutation in thyrocyte lines.


Transcript levels of proangiogenic factors were significantly lower in BRAF V600E PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF V600E mutation was induced (P=0.01) and increased when it was silenced (P=0.01).


Compared with BRAF-wt PTCs, those harboring BRAF V600E exhibit downregulated VEGFA, VEGFR, and PDGFR β expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.

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Marco Castellana, Giorgio Grani, Maija Radzina, Vito Guerra, Luca Giovanella, Maurilio Deandrea, Rose Ngu, Cosimo Durante and Pierpaolo Trimboli


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.


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.


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.


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.


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.