Background: Fine-needle aspiration cytology is frequently used for differential diagnosis of neck masses of unknown origin. Inconclusive and even false-negative results are not uncommon. Aim: To evaluate the utility of thyroglobulin (Tg) measurement in fine-needle aspirates (FNA-Tg) for detecting cervical lymph node (CLNs) metastases from differentiated thyroid carcinomas. Methods: An ultrasound-guided fine-needle aspiration was done in 67 patients with 83 suspicious enlarged CLNs to obtain material for cytology and Tg measurement in the needle washout, using an immunometric chemiluminescent assay. Measurement of anti-Tg antibodies (FNA-TgAb) was also carried out in half of all the aspirates. Subjects were divided into two groups: one of 16 patients awaiting thyroidectomy and the other of 51 patients in follow-up after surgery. Results: The first group of patients had positive FNA biopsy (FNAB-Tg) in 14 out of the 18 studied CLNs with a range of 3.2-43 352 ng/ml, while FNAB-cytology indicated metastasis in only 8 out of the 14 CLNs with positive histology. A total of 65 CLNs were studied in the follow-up group. Lymphadenectomy was performed in 23 patients and 28 aspirated CLNs were removed. Histology confirmed the diagnosis of metastasis suggested by FNAB-Tg in 20 CLNs and of reactive lymphadenitis in the remaining 8 CLNs. FNAB-cytology was positive in only 11 CLNs. Sensitivity of FNAB-Tg was not affected by the studied FNAB-TgAb. Conclusions: The FNAB-Tg achieved a sensitivity of 100% in both groups. FNAB-Tg is an easy and inexpensive technique which proved to increase the diagnostic of cytology in the early diagnosis of papillary carcinoma recurrence to CLN even in the presence of serum TgAb.
The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells.
Objective: Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in RET-and RAS-mutated MTC. Materials and methods: In this study, we analysed the presence of RET, H-RAS, and K-RAS mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation -using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) -by immunohistochemistry. Results: Our results revealed that RET mutations were present in 52.9% of the cases (46/87) and RAS mutations in 12.6% (11/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of RET and RAS mutations was mutually exclusive. RAS mutations were significantly associated with higher intensity of p-S6 expression (PZ0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (PZ0.042) and in MTCs with lymph node metastases (PZ0.046). Cytoplasmic PTEN expression was detected in 58.8% of the cases; cases WT for RAS showed a significantly lower expression of PTEN (PZ0.045). Conclusions: We confirmed the presence of RAS mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC.
Linkage studies have identified susceptibility loci for familial nonmedullary thyroid cancer (FNMTC), with and without cell oxyphilia, at chromosomal regions 19p13.2 and 2q21. There are few genetic analyses of FNMTC tumours reported at the present time and the eventual gene involved was not identified yet. The aim of this study was to assess the occurrence of loss of heterozygosity (LOH) at these loci in the tumours from familial clusters of NMTC. We have analysed LOH in 14 tumours from 9 two-case familial clusters of NMTC. Using paired blood (normal) and tumour DNA samples, we have genotyped ten microsatellite and one SNP markers throughout 19p13.2 and fourteen microsatellite markers at 2q21. Overall, eight (57%) and two (14%) out of the fourteen tumours analysed exhibited LOH at 19p13.2 and 2q21, respectively. In two families (22%), LOH for the same markers was demonstrable in the tumours of the two members of the same family. In one family (11%) LOH was demonstrable at both loci analysed. In four two-case familial clusters (44%), LOH at the 19p13.2 locus was found in only one of the tumour cases analysed. Detailed haplotype analysis showed that, in two families (22%), the pattern of LOH in tumours was consistent with selective retention of the haplotype shared by affected members. In the remaining cases, it was consistent with random allelic losses. In conclusion, we report the finding of LOH at the 19p13.2 and 2q21 loci in tumours from familial clusters of NMTC, providing evidence that inactivation of putative genes in these regions, acting as tumour-suppressors, may be involved in the development of tumours in the context of FNMTC.
The significance of RET in thyroid cancer comes from solid evidence that, when inherited, an RET activating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. The RET gene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature of RET point mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs.
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