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The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

Thyroid nodules are very common, affecting 19%-67% of the adult population. However, about 10% of them harbor a malignant lesion. Consequently, the first aim in their clinical evaluation is to exclude malignancy. Fine-needle aspiration cytology (FNAC) represents the main diagnostic tool for the evaluation of thyroid nodules. However, FNAC has a main diagnostic limit, namely cellular atypias of indeterminate significance, which require surgical excision and histological examination to differentiate benign from malignant lesions. Histology reports show that approximately 80% of these patients harbor a benign lesion. Therefore, in order to reduce unnecessary thyroidectomy, over the last years, the cytological classification of thyroid nodules has been revised and a number of new instrumental and molecular approaches have been proposed. In the present article, we will attempt to summarize the most recent cytological, molecular and echographic strategies to enhance the diagnostic accuracy of preoperative thyroid follicular lesions. In particular, we will discuss the new cytological classifications from the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), the British Thyroid Association-Royal College of Pathologists (PTA-RCPath) and the new Italian Society for Anatomic Pathology and Cytology (SIAPEC 2014. We will review molecular tests evaluated to ameliorate follicular lesion diagnosis as well as the clinical utility of the new echographic Thyroid Imaging Reporting and Data System (TI-RADS) score., (Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p < 0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The most appropriate surgical management of "follicular neoplasm/suspicious for follicular neoplasm" lesions (FN), considering their low definitive malignancy rate and the limited predictive power of preoperative clinic-diagnostic factors, is still controversial. On behalf of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB), we collected and analyzed the experience of 26 endocrine centers by computerized questionnaire. 1379 patients, surgically treated after a FN diagnosis from January 2012 and December 2103, were evaluated. Histological features, surgical complications, and medium-term outcomes were reported. Total thyroidectomy (TT) was performed in 1055/1379 patients (76.5 %), while hemithyroidectomy (HT) was carried out in 324/1379 cases (23.5 %). Malignancy rate was higher in TT than in HT groups (36.4 vs. 26.2 %), whereas the rates of transient and definitive hypoparathyroidism following TT were higher than after HT. Consensual thyroiditis (16.8 vs. 9.9 %) and patient age (50.9 vs. 47.9 %) also differed between groups. A cytological FN diagnosis was associated to a not negligible malignancy rate (469/1379 patients; 34 %), that was higher in TT than in HT groups. However, a lower morbidity rate was observed in HT, which should be considered the standard of care in solitary lesions in absence of specific risk factors. Malignancy could not be preoperatively assessed and clinical decision-making is still controversial. Further efforts should be spent to more accurately preoperatively classify FN thyroid nodules.

The three members of the Aurora kinase family, Aurora-A, -B and -C, regulate several aspects of the mitotic process, and their aberrant expression and/or function causes mitotic abnormalities leading either to cell death or aneuploidy. They are found overexpressed in several human malignancies, including the papillary thyroid carcinoma (PTC). In the present study, we sought to establish whether Aurora kinase inhibition could be of any therapeutic value in the treatment of aggressive forms of PTC, enduring to radioactive iodide (RAI) ablation. To this end, the effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on 3 human PTC cell lines expressing either wild-type (K1 and TPC1) or mutant p53 (BCPAP). The two inhibitors were capable of reducing cell proliferation in a time- and dose-dependent manner, with IC₅₀ comprised between 65.4 and 114.9 nM for MLN8237, and between 26.6 and 484.6 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited Aurora-B phosphorylation of histone H3 on Ser10, however, it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Time-lapse videomicroscopy evidenced that both inhibitors prevented the completion of cytokinesis, and cytofluorimetric analysis showed accumulation of cells in G2/M phase and/or polyploidy. Apoptosis was induced in all the cells by both inhibitors independently from the p53 status. In conclusion, in the present preclinical study MLN8237 and AZD1152 have emerged as promising drug candidates for RAI-insensitive PTC.

Small Ubiquitin–like MOdifier (SUMO) proteins are small protein modifiers capable of regulating cellular localization and function of target proteins. Over the last few years, a relevant role has been demonstrated for sumoylation in the modulation of important cellular processes, including gene transcription, DNA repair, cell-cycle regulation and apoptosis. Components of the sumoylation machinery have been found deregulated in different human cancers, and are thought to significantly affect cancer cell progression. In the present study we sought to analyze the expression of all the components of the sumoylation machinery in a case study comprising 77 papillary thyroid cancers (PTC) and normal matched tissues. In particular, we evaluated the expression of the SENP1 to SENP8 (SENtrin-specific proteases), SAE1 (SUMO1 activating enzyme subunit 1), UBA2 (UBiquitin-like modifier activating enzyme 2), UBC9 (UBiquitin conjugating enzyme 9), RanBP2 (RAN binding protein 2), MSMCE2 (Non- SMC element 2), CBX4 (ChromoBoX homolog 4), PIAS1 to PIAS4 (protein inhibitor of activated STAT), ZMIZ1 (zinc finger, MIZ-type containing 1) and ZMIZ2 (Zinc finger, MIZ-type containing 2) by means of quantitative RT-PCR. In most of the PTC examined we observed a significant alteration in the mRNAs of SENP8, ZMIZ1, SAE1, PIAS1 and PIAS2. These tended to be reduced in about 50 to 66% of cases, and unchanged or increased in the remaining ones. Univariate and Kaplan-Mayer analyses documented the lack of association between the expression of the above 5 genes and clinicopathological parameters. Only SAE1 was significantly higher in female PTC tissues, in respect to male PTC tissues (p=0.021), and SENP8 was significantly lower in TNM stages III-V, with respect to stages I-II (p=0.047). In conclusion, we demonstrated that the expression of SENP8, SAE1, PIAS1, PIAS2 and ZMIZ1 is deregulated in the majority of PTC tissues, likely contributing to the PTC phenotype. However, differently from other human cancers, their mRNA level does not represent a prognostic biomarker in PTC patients.

A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, but no information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, we evaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up- or down-regulated in the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed.A significant positive correlation between Aurora-A and Aurora-B mRNAs was observed (p=0.001). The expression of both Aurora genes was not affected by the BRAFV600E mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameters such as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well as disease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker in PTC patients.

Aims of the Study: The aim of this retrospective study was to appraise the impact of central neck dissection (CND) when treating papillary thyroid carcinoma (PTC) and identifying predictors of tumour recurrence by analysing the results and complications related to this surgical procedure., Materials and Methods: The study examined the histories of 347 patients with PTC, divided into two groups: group A including 284 patients who underwent total thyroidectomy (TT) only; group B including 63 patients who underwent TT and CND and possible lateral neck dissection (LND)., Results: The patients in the B group were younger than those in the A group (an average of 44.5 vs. 48.6; p = 0.03) and their tumours were larger (1.91 cm vs 1.27 cm, p = 0.001). Multifocality, extra-capsular extensions of the neoplastic mass and high cell histological variant were more prevalent in the B group. The incidence of permanent hyperparathyroidism was higher in group B than in group A (25.4% vs 9.5%, p = 0.0006). Recurrence of disease and the numbers requiring reoperation were also higher in group B: (24.1% in group B vs 6.6 in group A, p < 0.0001). Patients classified as clinically N0 at their first operation and who were most probably clinically N1, totalled 6.6%., Conclusions: Our data show that only extra-capsular extension may be considered a predictor of recurrence. The findings of our study support the idea of carrying out "therapeutic" CND only in cases of preoperative or macroscopic intraoperative clinical evidence of lymph-node involvement., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

The present study aims to investigate the feasibility and influence of the lymphatic mapping and sentinel node biopsy on determination of the nodal status in thyroid carcinoma using blue-dye method. Nine consecutive patients with cytological diagnosis of papillary carcinoma were included in this study. To detect the sentinel lymphnode, intra- or perinodular injection of an average quantity of 0.5 ml (range : 0.1-1.2) of Ble Patenté V was performed intraoperatively in 8 cases only, as in one case a solitary cystic nodule occupied the entire lobe and thus any injection was impossible. After an average time of 16 minutes (range : 5-25) before dissection of the thyroid , no lymphnodes and no lymphatic afferent thereto visibly coloured were evidenced, except for spread of the vital dye into adjacent tissue and disrupted blood and lymphatic vessels at the injection site. Our results evidence that : intranodular injection, does not allow proper diffusion of the dye in the adjacent parenchyma, and in nodules smaller than 1 cm it may be difficult ; and that it is hazardous in cystic nodule because of the rupture risk; perinodular injection, at the four cardinal points, is impossible when the nodule occupies the entire lobe or the isthmus; multinodular goiter complicates the identification by palpation of the neoplastic nodule in which the dye should be injected or, if perinodular injection is given, to detect the parenchyma surrounding the nodule.

Cellular fibronectins containing the extracellular domain A or B (EDA and EDB) are particularly abundant in fetal and neoplastic tissues. The presence of EDA and EDB was investigated in 28 cases of papillary carcinoma of the thyroid using IST-9 and BC-1 monoclonal antibodies. Immunostaining for EDA and EDB was detected in tumour stroma, in tumour basement membranes, and in tumour blood vessels. EDA was present in 27 of the 28 cases, in 20 of which more than 75 per cent of the tumour stroma was stained. Immunostaining for EDB was detected in 23 of the 28 cases and was less pronounced than that for EDA, being present in less than 25 per cent of the tumour stroma in most cases. Reactivity for EDA/EDB was not observed in the adjacent normal thyroid in any of the cases investigated. In a group of 20 non-papillary tumours, immunostaining for EDA was present in the stroma of three follicular carcinomas (one minimally and two widely invasive), one medullary carcinoma, and 5 of 16 follicular adenomas; expression of EDB was more restricted, being present in only the two cases of widely invasive follicular carcinoma. The presence of EDA and EDB was not correlated with the extent of fibrosis or the degree of tumour cell differentiation. Immunoreactivity was already present in microcarcinomas. These observations raise the possibility that the production of oncofetal fibronectins is an important step in papillary carcinoma tumourigenesis, perhaps facilitating adhesion and spreading of tumour cells., (Copyright 1999 John Wiley & Sons, Ltd.)

The authors report their experience and surgical treatment of 440 patients with differentiated carcinoma of the thyroid (DCT) from 1970 to 1990 in the III Surgical Dept. at the University of Rome "La Sapienza". Considering 305 cases of papillary carcinoma, 103 Total Thyroidectomy (TT), 118 TT with Functional Regional Lymphadenectomy (FRL), 32 TT with Node-Picking, 51 TT with curative FRL and one TT with Radical Neck dissection were performed. In 135 cases of follicular carcinoma TT associated with Node-picking were performed on two patients, TT associated with FRL on 8 patients and TT associated with RND on 2 patients. Overall survival to 10 years was 90%; 98% for N- papillary carcinoma and 66% for N+ follicular carcinoma. There were no permanent recurrence of disease. Out of the patients who did not undergo cervical lymphadenectomy 30% developed temporary hypocalcemia; 53% (mediastinal lymphadenectomy) to 87% (FRL) of the patients submitted to lymphadenectomy developed temporary hypocalcemia with permanent hypoparathyroidism in 0.9%-23% of the cases. On the base of what has been observed by Pasieka and Grant, the Authors believe TT as the absolute solution for patients with DCT because it allows the removal of both the original tumor and the possible neoplasms in the residual gland tissue, and enables early identification of other metastases which can be treated efficaciously with I131.