No abstract

Fine-needle aspiration biopsy (FNAB) is an accurate, slightly invasive, and safe method for the preoperative diagnosis of thyroid nodules. Recently, ultrasound guidance has been suggested as a valuable aid to enhance FNAB diagnostic performance. In this study, we have compared diagnostic accuracy of conventional FNAB (C-FNAB) versus sonography-guided FNAB (SG-FNAB) on a large sample population of 9683 patients with thyroid nodules. Over a 15-year period, 4986 patients were investigated by C-FNAB and 4697 underwent SG-FNAB. A valid cytological diagnosis was obtained in 85.9% of C-FNAB and in 91.5% of SG-FNAB cases, allowing detection of thyroid cancer in 1.6% and 2.1% of patients, respectively. The indeterminate pattern of follicular neoplasia was observed in 238 C-FNAB (5%) and in 272 (5.4%) SG-FNAB nodules. Specimens were cytologically inadequate in 433 C-FNAB (8.7%), but only in 167 SG-FNAB cases (3.5%). A total of 535 C-FNAB and 540 SG-FNAB nodules underwent surgery. False-negative results occurred in 7 C-FNAB nodules (2.3%), but only in 3 SG-FNAB cases (1%). Sensitivity, specificity, and global diagnostic accuracy of C-FNAB compared with SG-FNAB were 91.8% versus 97.1%, 68.8% versus 70.9%, and 72.6% versus 75.9%, respectively. Our results, based on a large population of thyroid nodules, demonstrate that SG-FNAB allows a more precise and adequate sampling of thyroid nodular lesions and is associated with a lower rate of false-negatives, thus improving global diagnostic accuracy in the preoperative selection of thyroid cancer.

TM is a rare event, is more frequent in patients older than 60 years, and has the same impact on prognosis as nonthyroidal metastases. Although thyroidectomy may be useful to avoid further dissemination of the primary tumour in case of solitary TM, it does not contribute to prolonging patient's life.

Activating mutations of BRAF have been identified in a variety of human cancers, most notably melanomas and papillary thyroid carcinomas (PTCs). The aim of the present study was to disclose the role of BRAF mutations in thyroid carcinoma development.Seventy-two thyroid tumors, including 60 PTCs, six follicular adenomas, five follicular carcinomas, and one anaplastic carcinoma, were studied. BRAF mutation screening focused on exon 15 and exon 11 of the gene by single-stranded conformational polymorphism and sequence analysis. Search of RET/PTC expression was conducted with the RT-PCR technique.The molecular genetic study of the BRAF gene showed the presence of a missense thymine to adenine transversion at nucleotide 1796, resulting in the V599E substitution, in 24 of 60 PTCs (40%), none of six follicular adenomas, and none of five follicular carcinomas or one anaplastic carcinoma. Moreover, nine of 60 PTCs (15%) presented RET/PTC expression. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P ‫؍‬ 0.038). On the contrary, no link could be detected between expression of BRAF V599E and age at diagnosis, gender, dimension, and local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, and multifocality of the disease.These data clearly confirm that BRAF V599E is the more common genetic alteration found to date in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype. (J Clin Endocrinol Metab 89: 2414 -2420, 2004)

The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

In mammals, molecular mechanisms and factors involved in the tight regulation of telomerase expression and activity are still largely undefined. In this study, we provide evidence for a role of estrogens and their receptors in the transcriptional regulation of hTERT, the catalytic subunit of human telomerase and, consequently, in the activation of the enzyme. Through a computer analysis of the hTERT 5-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro human estrogen receptor ␣ (ER␣). In vivo DNA footprinting revealed specific modifications of the ERE region in ER␣-positive but not ER␣-negative cells upon treatment with 17␤-estradiol (E2), indicative of estrogen-dependent chromatin remodelling. In the presence of E2, transient expression of ER␣ but not ER␤ remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. No telomerase activity was detected in human ovary epithelial cells grown in the absence of E2, but the addition of the hormone induced the enzyme within 3 h of treatment. The expression of hTERT mRNA and protein was induced in parallel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of the hTERT gene. The identification of hTERT as a target of estrogens represents a novel finding which advances the understanding of telomerase regulation in hormone-dependent cells and has implications for a potential role of hormones in their senescence and malignant conversion.Most human somatic cells do not express telomerase, the ribonucleoprotein that elongates telomeric DNA, or its catalytic protein, hTERT, which is limiting for enzyme activity (33). In humans, telomerase is regulated in a tissue-specific manner during development (42); the enzyme is present in early embryogenesis but is repressed upon cell differentiation in somatic tissues (27,42). Loss of enzymatic activity is accompanied by loss of the full-length transcript of hTERT and/or by the appearance of alternatively spliced transcripts that are unlikely to encode functional proteins (21, 42). In the adult, telomerase persists only in germ line cells and in progenitor cells of somatic tissues with self-renewing potential, in agreement with the requirement for the enzyme for sustained cell proliferation (16). How hTERT silencing is achieved and which factors contribute to this process are presently unknown, although the regulation of hTERT expression appears to be primarily at the transcriptional level (42). An understanding of the molecular mechanisms underlying the regulation of telomerase activity might allow the modulation of telomerase expression and, consequently, of cell life span (4, 43), with important potential therapeutic applications in aging and malignancy.Several lines of evidence suggest that sex steroid hormones may be good candidates as physiological regulators of hTERT expression. Recent findings are consistent with the hypothesis that te...

Although B-Raf V600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-Raf V600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-Raf V600E -positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-Raf V600E resulted in TSP-1 downregulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-Raf V600E cells in which either B-Raf V600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-Raf V600E , caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-Raf V600E plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patient's thyroid cancer for B-Raf V600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-Raf V600E inhibitors, such as PLX4720. extracellular matrix | metastasis | papillary thyroid cancer | tumor microenvironment | cell invasion P apillary thyroid cancer (PTC), with its incidence increasing by almost 5% each year, currently ranks as the eighth most common malignancy diagnosed in women (1). Neck recurrences alone are responsible for a third of thyroid cancer-related deaths. There is no effective treatment for radioiodine-resistant metastatic disease; the 10-year survival rate in these cases is only 10% (2). Molecular understanding of the aggressive clinical behavior of this subset of patients is needed to develop new therapeutic options.

KEY WORDS: Liquid-based cytology; noninvasive follicular variant of papillary thyroid cancer; noninvasive follicular thyroid neoplasm with papillary-like nuclear features; thyroid carcinoma; thyroid lesions. INTRODUCTIONOver the last decades, the exact nature of thyroid lesions diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) has been debated. [1][2][3][4][5][6][7][8] Specifically, FVPTCs appear to represent a heterogeneous group of carcinomas and a controversial entity including both encapsulated/noninvasive (NI-FVPTCs) and invasive FVPTCs Based on their multi-institutional histological series, the Endocrine International Working Group recommended the reclassification of these NI-FVPTCs as "noninvasive follicular thyroid neoplasm with papillarylike nuclear features" (NIFTP). This entity was defined by a set of morphological features including nuclear membrane irregularities, ground glass appearance of the nuclei, and larger nuclear size within a context of encapsulated follicular tumor. 10 Conversely, apart from the histological approach and definition of these NIFTPs, its cytological diagnosis is still under evaluation in that this new terminology might significantly affect both the diagnosis of thyroid lesions and the categories of the different cytological classification systems. [11][12][13][14][15][16][17][18] For these reasons, and because none of the classification systems, including The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), accounts for the allocation of NIFTPs, it is crucial to establish in which cytological categories NIFTPs should be diagnosed. 19-23Therefore, a growing number of studies currently are investigating whether these lesions can be identified by fine-needle aspiration (FNA) and more specifically their impact on the ROM in the different diagnostic categories. Nevertheless, currently, the majority of FVPTCs are frequently diagnosed in the cytological categories of follicular neoplasm (FN) or suspicious for malignancy (SM) due to the absence of the undoubtedly nuclear features of PTCs, which may support a conclusive malignant diagnosis. [11][12][13][14][15][16][17][18] For this reason, some authors have analyzed their cytological cases for specific features able to identify the correct cytological categories for NIFTPs. Despite the small number of published series regarding NIFTPs to date, the preliminary results have demonstrated that the presence of nuclear pseudoinclusions and papillary structures are typical features of PTCs whereas a predominantly follicular pattern may be linked to NIFTPs, even if all these authors have not found any differentiation between NIFTPs and I-FVPTCs on FNA. Thus, the purpose of the current study was to examine and compare the morphological features in a series of cytohistological cases processed with liquid-based cytology (LBC) and diagnosed as either NIFTPs or I-FVPTCs. To the best of our knowledge, this study represents the first and largest series on LBC cytology published to date in which all the architectura...