الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Thyroid nodules are a common clinical finding, and they are also found more commonly by ultrasonography examination of the thyroid gland, and estimated to reach 12 to 35 % among the adult population. Fortunately, the vast majority of thyroid nodules are benign. However the risk of malignancy, representing 5-15% of all thyroid nodules, remains the main medical concern in the management of any discovered thyroid nodule.
Thyroid cancer accounts for 90% of the endocrine cancers and its incidence is increasing. In Egypt, thyroid cancer represents the 5th most common cancer among females in Lower Egypt, with a an age-standardized rate (ASR) of 5.4 as well as the 6’h commonest cancer among the total Egyptian females with an ASR of 4.3, and as worldwide, it is much lower among males.
The current workup of thyroid nodules involves stepwise escalating tools, including the clinical examination, thyroid hormones measurement, ultrasonography, scintigraphy, and fine-needle aspiration cytology (FNAC). However, this workup is still incomplete, and ends up by referring a considerable proportion of nodule-holding patients to unnecessary thyroidectomy with its medical and economical impacts, where more than 50 % of resected nodules prove to be benign by post-thyroidectomy histopathological examination.
The imperfect current practice is attributed to the limitations of FNAC, where nearly in 30 % of aspirations it comes out with nondiagnostic” (ND) or ”unsatisfactory” (UNS) as it fails to meet the established qualitative or quantitative criteria for cytologic adequacy, and the undetermined cytology group carrying a risk of malignancy of 15 %. As well, FNAC incapability to distinguish benign follicular lesions (follicular adenoma; the most common benign thyroid nodule) from follicular carcinomas, as they have cytologically a very similar appearance and need for differentiation, the demonstration of follicular cell invasion of the tumor capsule and/or blood vessels, by pathological examination of a surgical excision biopsy. This in addition to the false positive rate of FNAC, and the reported as suspicious for malignancy carries a risk of malignancy of 60 to 75 %.
Motivated by the need for an additional diagnostic tool, the idea for evaluating the serum biomarkers profile as a tool to discriminate malignant from benign thyroid nodules, has raised. The resorting to serum profiling as a valuable diagnostic tool, has been considered and proved before in cancers of the colon, stomach, pancreas and lung. Combined biomarkers panel augments the diagnostic performance, increasing the sensitivity, specificity and predictive values of the individual biomarker.
The aim of this work was to evaluate the utility of serum biomarkers profiling (interleukin-5, interleukin-8, hepatocyte growth factor, epidermal growth factor, angiopoietin-1, galectin-3, monokine induced by interferon-gamma, and vitamin D binding protein), to differentiate malignant from benign thyroid nodules.
The eight serum biomarkers chosen for evaluation as the aim of this study were selected based on their proved roles in cancer pathogenesis and specific involvements in thyroid oncogenesis, including cellular proliferation, inhibition of apoptosis leading to cell survival, tissue invasion, angiogenesis and neovascularization, epithelial-mesenchymal transition, migration and metastasis and also anti-tumor pro-inflammatory activity.
Summary
Selection was based also for some markers on documented over-expression in thyroid
cancer tissue, and/or a preceding finding of a differential serum level of an individual
marker, among thyroid cancer patients.
The analysis of combined biomarkers panels requires a multiplex technique, which allows saving time, effort and expenses. Hence, the multiplex bead assay (Luminex technology) was chosen to accomplish this target.
The current study was conducted on 60 subjects of three groups (of 20 each); healthy control, benign thyroid nodule, and malignant thyroid nodule. Thyroid nodules were subjected to ultrasound imaging, FNAC, and post-operative hystopathological examination. Serum levels of the eight selected biomarkers were determined for all subjects included in the study.
The data reached were analysed by the appropriate statistical tests, ROC curves were constructed and tables of agreement and diagnostic performance were performed for individual markers and combinations, to evaluate the suggested capability of the serum biomarkers profile to achieve a discriminative tool for malignancy in thyroid nodules.
from the present study the following results were obtained:
Total thyroid nodules as well as the malignant ones - in accordance with the
worldwide and Egyptian data are more common among females.
A major proportion (71 % in the present study) of operated Bethesda III and IV
thyroid nodules, proved to be benign by post-operative histopathological examination.
Serum interleukin-8 (IL-8) levels were significantly higher (p<0.001) among patients with malignant thyroid nodules in comparison to those with benign nodules. IL-8 ROC curve to discriminate malignant from benign thyroid nodules revealed an AUC of 0.849.
Serum epidermal growth factor (EGF) levels were significantly higher (p<0.001) among patients with malignant thyroid nodules in comparison to those with benign nodules. EGF ROC curve to discriminate malignant from benign thyroid nodules revealed an AUC of 0.848.
Serum hepatocyte growth factor (HGF), monokine induced by interferon gamma (MIG), and angiopoietin-1 (Ang-1) levels were significantly higher among patients with malignant thyroid nodules in comparison to those with benign nodules. (p
0.012, 0.023, and 0.014 respectively)
HGF, MIG and Ang-1 showed individually less discriminative capability than IL-
8 and EGF. ROC curves to discriminate malignant from benign thyroid nodules, of HGF, MIG and Ang-1 revealed AUC of 0.728, 0.726, and 0.725 respectively.
There were no statistically significant differences in serum levels of interleukin-5, galectin-3, or vitamin D binding protein between patients with malignant and benign thyroid nodules.
Although the different biomarkers combinations did not augment the overall diagnostic performance (represented by the AUC of the ROC curve), higher than the
Summary
performance of the IL-8 or EGF individually, markers combination has significantly raised the negative predictive value (NPV) of any of the markers individually.
NPV, chosen as the most valuable performance index in the additional diagnostic tool needed to confirm the benign nature of a thyroid nodule and to save patients unnecessary thyroidectomy, raised from 76.2% for IL-8 and 85% for EGF to 92.86% by combination of both.
Three-marker combination (IL-8 + EGF + HGF) and the four-marker combination (IL-8 + EGF + HGF + MIG) have achieved NPP of 100% and sensitivity of 100%, to discriminate benign and malignant nodules. This was associated with a reduction in the specificity (proportion of benign-nodule patients able to profit the negative test).
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