Benign Follicular Thyroid Adenoma Research Articles

Identification of Diagnostic Metabolic Signatures in Thyroid Tumors Using Mass Spectrometry Imaging.

"Gray zone" thyroid follicular tumors are difficult to diagnose, especially when distinguishing between benign follicular thyroid adenoma (FTA) and malignant carcinoma (FTC). Thus, proper classification of thyroid follicular diseases may improve clinical prognosis. In this study, the diagnostic performance of metabolite enzymes was evaluated using imaging mass spectrometry to distinguish FTA from FTC and determine the association between metabolite enzyme expression with thyroid follicular borderline tumor diagnosis. Air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFAIDESI-MSI) was used to build a classification model for thyroid follicular tumor characteristics among 24 samples. We analyzed metabolic enzyme marker expression in an independent validation set of 133 cases and further evaluated the potential biological behavior of 19 thyroid borderline lesions. Phospholipids and fatty acids (FAs) were more abundant in FTA than FTC (p < 0.001). The metabolic enzyme panel, which included FA synthase and Ca2+-independent PLA2, was further validated in follicular thyroid tumors. The marker combination showed optimal performance in the validation group (area under the ROC, sensitivity, and specificity: 73.6%, 82.1%, and 60.6%, respectively). The findings indicate that AFAIDESI-MSI, in combination with low metabolic enzyme expression, could play a role in the diagnosis of thyroid follicular borderline tumors for strict follow-up.

Current surgical management of follicular thyroid carcinoma

: Follicular thyroid carcinoma (FTC) comprises a heterogenous group of tumors, which divides into subtypes with different malignant potential: minimally invasive (excellent prognosis), encapsulated angioinvasive and widely invasive FTC (higher risk metastasis and recurrence). Numerous clinical risk factors (presence of metastases, advanced patient age, tumor size and others), which can be used to assess FTC aggressiveness, are discussed with regard to the present literature. The definitive characterization of follicular neoplasms depends on postoperative histology, due to the incapability of preoperative imaging, fine-needle aspiration cytology or molecular analysis to clearly distinguish between FTC and benign follicular thyroid adenoma. In this review, treatment strategies for FTC (according to the WHO 2017 classification of endocrine neoplasms) are presented, as recommended by the leading expert societies American Thyroid Association (ATA), British Thyroid Association (BTA), German Society of Endocrine Surgery (CAEK) and European Society of Endocrine Surgery (ESES). Hemithyroidectomy is sufficient in low-risk FTC (capsular invasion only). Thyroidectomy with postoperative radioiodine therapy is recommended for high-risk FTCs (angioinvasion; widely invasive histology). Prophylactic lymphadenectomy is not necessary. Considering clinical risk factors, an individual surgical approach should be chosen, following a stepwise, escalating surgical management with restricted primary resection (hemithyroidectomy) and, if necessary, completion surgery based on the definitive histopathology.

Network-Based Genetic Profiling Reveals Cellular Pathway Differences Between Follicular Thyroid Carcinoma and Follicular Thyroid Adenoma.

Molecular mechanisms underlying the pathogenesis and progression of malignant thyroid cancers, such as follicular thyroid carcinomas (FTCs), and how these differ from benign thyroid lesions, are poorly understood. In this study, we employed network-based integrative analyses of FTC and benign follicular thyroid adenoma (FTA) lesion transcriptomes to identify key genes and pathways that differ between them. We first analysed a microarray gene expression dataset (Gene Expression Omnibus GSE82208, n = 52) obtained from FTC and FTA tissues to identify differentially expressed genes (DEGs). Pathway analyses of these DEGs were then performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) resources to identify potentially important pathways, and protein-protein interactions (PPIs) were examined to identify pathway hub genes. Our data analysis identified 598 DEGs, 133 genes with higher and 465 genes with lower expression in FTCs. We identified four significant pathways (one carbon pool by folate, p53 signalling, progesterone-mediated oocyte maturation signalling, and cell cycle pathways) connected to DEGs with high FTC expression; eight pathways were connected to DEGs with lower relative FTC expression. Ten GO groups were significantly connected with FTC-high expression DEGs and 80 with low-FTC expression DEGs. PPI analysis then identified 12 potential hub genes based on degree and betweenness centrality; namely, TOP2A, JUN, EGFR, CDK1, FOS, CDKN3, EZH2, TYMS, PBK, CDH1, UBE2C, and CCNB2. Moreover, transcription factors (TFs) were identified that may underlie gene expression differences observed between FTC and FTA, including FOXC1, GATA2, YY1, FOXL1, E2F1, NFIC, SRF, TFAP2A, HINFP, and CREB1. We also identified microRNA (miRNAs) that may also affect transcript levels of DEGs; these included hsa-mir-335-5p, -26b-5p, -124-3p, -16-5p, -192-5p, -1-3p, -17-5p, -92a-3p, -215-5p, and -20a-5p. Thus, our study identified DEGs, molecular pathways, TFs, and miRNAs that reflect molecular mechanisms that differ between FTC and benign FTA. Given the general similarities of these lesions and common tissue origin, some of these differences may reflect malignant progression potential, and include useful candidate biomarkers for FTC and identifying factors important for FTC pathogenesis.

Comparison between patients with thyroid follicular tumors in the histological pattern and size of follicular lesion

The main problem encountered in thyroid nodule is difficult to differentiate between a benign and malignant lesion. Differential between follicular thyroid cancer (FTC) and benign follicular thyroid adenoma (FTA) is a great challenge for even an experienced pathologist and requires special effort. A total of 120 paraffin block were included in the study, 30 blocks were (FC), 30 blocks were (FVPC). 30 blocks were (FA), 30 blocks were blocks thyroid follicular hyperplasia.20 blocks endocervical epithelium.20 paraffin blocks of colonic epithelium as control. From each paraffin block, 4 slides, each of thicken were taken, stained with Hematoxylin and Eosin (H&amp;E) for revision of histopathological diagnosis. The histological arrangement in follicular carcinoma and follicular adenoma was significant (P= 0.001) in trabecular pattern and the difference was significant (P= 0.016) in mixed pattern while no significance with microfollicular, macrofollicular and normofollicular pattern in both follicular carcinoma and adenoma. There was no significant difference in size follicular lesion among FA, FVPC and follicular hyperplasia (P&gt; 0.05) while, the size follicular lesion in of (FC) was significantly higher from all other groups (P&lt; 0.05).

Comparison between patients with thyroid follicular tumors in the histological pattern and size of follicular lesion

The main problem encountered in thyroid nodule is difficult to differentiate between a benign and malignant lesion. Differential between follicular thyroid cancer (FTC) and benign follicular thyroid adenoma (FTA) is a great challenge for even an experienced pathologist and requires special effort.A total of 120 paraffin block were included in the study, 30 blocks were (FC), 30 blocks were (FVPC). 30 blocks were (FA), 30 blocks were blocks thyroid follicular hyperplasia.20 blocks endocervical epithelium.20 paraffin blocks of colonic epithelium as control. From each paraffin block, 4 slides, each of thicken were taken, stained with Hematoxylin and Eosin (H&amp;E) for revision of histopathological diagnosis.The histological arrangement in follicular carcinoma and follicular adenoma was significant (P= 0.001) in trabecular pattern and the difference was significant (P= 0.016) in mixed pattern while no significance with microfollicular, macrofollicular and normofollicular pattern in both follicular carcinoma and adenoma. There was no significant difference in size follicular lesion among FA, FVPC and follicular hyperplasia (P&gt; 0.05) while, the size follicular lesion in of (FC) was significantly higher from all other groups (P&lt; 0.05).

Detection of PAX8/PPAR fusion gene by FISH Technique in follicular thyroid lesions

The main problem established by a discovery of a thyroid nodule is to discriminate between a benign and malignant lesion. Differential diagnosis between follicular thyroid cancer (FTC) and benign follicular thyroid adenoma (FTA) is a great challenge for even an experienced pathologist and requires special effort.The purpose of the study was to detect PAX8/PPAR G gene rearrangement by fluorescent in situ hybridization (FISH) technique,the present study is the first time in Iraq used this technique to detect fusion gene in follicular thyroid lesions,follicular carcinoma (FC) follicular variant papillary of carcinoma (FVPC), follicular adenoma (FA) and follicular hyperplasia. A total of 120 paraffin block were included in the study,30 blocks were (FC),30 blocks were (FVPC). 30 blocks were (FA),30 blocks were blocks thyroid follicular hyperplasia.20 blocks endocervical epithelium.20 paraffin blocks of colonic epithelium. The clinicopathological parameters were obtained from patients’ admission case sheets and pathology reports (age,gender). The description of measures regarding fluorescent instu hybridization of PAX8/ PPAR G fusion gene there was significantly highest in follicular carcinoma,followed by follicular variant of papillary carcinoma,then follicular adenoma and lastly by follicular hyperplasia The area under the curve for all three markers was &gt;0.8.The p-value was highly significant for all three markers (P&lt;0.001). Cutoff values that predict malignant thyroid follicles lesion were as following: score of &gt;1 for Galectin-3 marker,score of &gt;2 for HBME-1 marker and number of positive cells per 50 of &gt;13 (&gt;26%) for PAX8 /PPAR G fusion gene marker. The sensitivities for the three markers were 100.00 %,90.00 % and 66.67 %,respectively,whereas the specificities were 88.30 %,98.33 % and 100.00 % respectively.

Analysis options for high-throughput sequencing in miRNA expression profiling

BackgroundRecently high-throughput sequencing (HTS) using next generation sequencing techniques became useful in digital gene expression profiling.Our study introduces analysis options for HTS data based on mapping to miRBase or counting and grouping of identical sequence reads. Those approaches allow a hypothesis free detection of miRNA differential expression.MethodsWe compare our results to microarray and qPCR data from one set of RNA samples. We use Illumina platforms for microarray analysis and miRNA sequencing of 20 samples from benign follicular thyroid adenoma and malignant follicular thyroid carcinoma. Furthermore, we use three strategies for HTS data analysis to evaluate miRNA biomarkers for malignant versus benign follicular thyroid tumors.ResultsHigh correlation of qPCR and HTS data was observed for the proposed analysis methods. However, qPCR is limited in the differential detection of miRNA isoforms. Moreover, we illustrate a much broader dynamic range of HTS compared to microarrays for small RNA studies. Finally, our data confirm hsa-miR-197-3p, hsa-miR-221-3p, hsa-miR-222-3p and both hsa-miR-144-3p and hsa-miR-144-5p as potential follicular thyroid cancer biomarkers.ConclusionsCompared to microarrays HTS provides a global profile of miRNA expression with higher specificity and in more detail. Summarizing of HTS reads as isoform groups (analysis pipeline B) or according to functional criteria (seed analysis pipeline C), which better correlates to results of qPCR are promising new options for HTS analysis. Finally, data opens future miRNA research perspectives for HTS and indicates that qPCR might be limited in validating HTS data in detail.

Molecular differential diagnosis of follicular thyroid carcinoma and adenoma based on gene expression profiling by using formalin-fixed paraffin-embedded tissues

BackgroundDifferential diagnosis between malignant follicular thyroid cancer (FTC) and benign follicular thyroid adenoma (FTA) is a great challenge for even an experienced pathologist and requires special effort. Molecular markers may potentially support a differential diagnosis between FTC and FTA in postoperative specimens. The purpose of this study was to derive molecular support for differential post-operative diagnosis, in the form of a simple multigene mRNA-based classifier that would differentiate between FTC and FTA tissue samples.MethodsA molecular classifier was created based on a combined analysis of two microarray datasets (using 66 thyroid samples). The performance of the classifier was assessed using an independent dataset comprising 71 formalin-fixed paraffin-embedded (FFPE) samples (31 FTC and 40 FTA), which were analysed by quantitative real-time PCR (qPCR). In addition, three other microarray datasets (62 samples) were used to confirm the utility of the classifier.ResultsFive of 8 genes selected from training datasets (ELMO1, EMCN, ITIH5, KCNAB1, SLCO2A1) were amplified by qPCR in FFPE material from an independent sample set. Three other genes did not amplify in FFPE material, probably due to low abundance. All 5 analysed genes were downregulated in FTC compared to FTA. The sensitivity and specificity of the 5-gene classifier tested on the FFPE dataset were 71% and 72%, respectively.ConclusionsThe proposed approach could support histopathological examination: 5-gene classifier may aid in molecular discrimination between FTC and FTA in FFPE material.

Discovery and Validation of Protein Abundance Differences between Follicular Thyroid Neoplasms

Distinguishing between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC) by cytologic features alone is not possible. Molecular markers may aid distinguishing FTA from FTC in patients with indeterminate cytology. The aim of this study is to define protein abundance differences between FTC from FTA through a discovery (proteomics) and validation (immunohistochemistry) approach. Difference gel electrophoresis (DIGE) and peptide mass fingerprinting were performed on protein extracts from five patients with FTC and compared with six patients with FTA. Individual gel comparisons (i.e., each FTC extract versus FTA pool) were also performed for the five FTC patients. Immunohistochemical validation studies were performed on three of the identified proteins. Based on DIGE images, 680 protein spots were matched on individual gels. Of these, 102 spots showed statistically significant differences in abundance between FTC and FTA in the individual gel analyses and were therefore studied further. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify 54 of these protein spots. Three candidates involved in protein folding (heat shock protein gp96, protein disulfide isomerase A3, and calreticulin) were studied by immunohistochemistry. Moderate calreticulin immunohistochemical staining was the best single marker with a high negative predictive value (88%); combining all three markers (any marker less than moderate staining) had the best positive predictive value (75%) while still retaining a good negative predictive value (68%). With DIGE, we identified 54 proteins differentially abundant between FTC and FTA. Three of these were validated by immunohistochemistry. These findings provide further insights into the diagnosis, prognosis, and pathophysiology of follicular-derived thyroid neoplasms.

Benign Struma Ovarii in a Patient With Invasive Papillary Thyroid Cancer: Detection with I-131 SPECT-CT

Abstract: A 78-year-old woman was referred for I-131 therapy following total thyroidectomy for invasive papillary thyroid cancer. The thyroglobulin titer was markedly elevated following thyroxine withdrawal, and she was given 5,550 MBq (150 mCi) of I-131 following additional pretreatment with rTSH (Thyrogen). A posttherapy scan showed intense, focal activity in the pelvis, which localized to the right ovary on SPECT-CT fusion examination. Contrast CT confirmed a cystic right ovarian tumor and she underwent laparoscopic oophorectomy, which revealed a benign follicular thyroid adenoma (struma ovarii). At 6-month follow-up, a whole body iodine scan was normal, and the TSH-stimulated thyroglobulin was undetectable.

Diagnosis of Suspicious Thyroid Nodules Using Four Protein Biomarkers

Fine-needle aspiration (FNA) cytology, a standard method for thyroid nodule diagnosis, cannot distinguish between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC). Previously, using expression profiling, we found that a combination of transcript expression levels from DDIT3, ARG2, C1orf24, and ITM1 distinguished between FTA and FTC. The goal of this study was to determine if antibody markers used alone or in combination could accurately distinguish between a wider variety of benign and malignant thyroid lesions in fixed sections and FNA samples. Immunohistochemistry was done on 27 FTA, 25 FTC, and 75 other benign and malignant thyroid tissue sections using custom antibodies for chromosome 1 open reading frame 24 (C1orf24) and integral membrane protein 1 (ITM1) and commercial antibodies for DNA damage-inducible transcript 3 (DDIT3) and arginase II (ARG2). FNA samples were also tested using the same antibodies. RNA expression was measured by quantitative PCR in 33 thyroid lesions. C1orf24 and ITM1 antibodies had an estimated sensitivity of 1.00 for distinguishing FTA from FTC. For the expanded analysis of all lesions studied, ITM1 had an estimated sensitivity of 1.00 for detecting malignancy. Because all four cancer biomarkers did well, producing overlapping confidence intervals, not one best marker was distinguished. Transcript levels also reliably predicted malignancy, but immunohistochemistry had a higher sensitivity. Malignant cells were easily detected in FNA samples using these markers. We improved this diagnostic test by adding C1orf24 and ITM1 custom antibodies and showing use on a wider variety of thyroid pathology. We recommend that testing of all four cancer biomarkers now be advanced to larger trials. Use of one or more of these antibodies should improve diagnostic accuracy of suspicious thyroid nodules from both tissue sections and FNA samples.

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression

Accurate diagnosis of thyroid tumors is challenging. A particular problem is distinguishing between follicular thyroid carcinoma (FTC) and benign follicular thyroid adenoma (FTA), where histology of fine-needle aspirates is not conclusive. It is often necessary to remove healthy thyroid to rule out carcinoma. In order to find markers to improve diagnosis, we quantified gene transcript expression from FTC, FTA, and normal thyroid, revealing 73 differentially expressed transcripts (P ≤ 0.0001). Using an independent set of 23 FTCs, FTAs, and matched normal thyroids, 17 genes with large expression differences were tested by real-time RT-PCR. Four genes (DDIT3, ARG2, ITM1, and C1orf24) differed between the two classes FTC and FTA, and a linear combination of expression levels distinguished FTC from FTA with an estimated predictive accuracy of 0.83. Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]). A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules, allowing better treatment decisions and reducing long-term health costs.

A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression.

Accurate diagnosis of thyroid tumors is challenging. A particular problem is distinguishing between follicular thyroid carcinoma (FTC) and benign follicular thyroid adenoma (FTA), where histology of fine-needle aspirates is not conclusive. It is often necessary to remove healthy thyroid to rule out carcinoma. In order to find markers to improve diagnosis, we quantified gene transcript expression from FTC, FTA, and normal thyroid, revealing 73 differentially expressed transcripts (P < or = 0.0001). Using an independent set of 23 FTCs, FTAs, and matched normal thyroids, 17 genes with large expression differences were tested by real-time RT-PCR. Four genes (DDIT3, ARG2, ITM1, and C1orf24) differed between the two classes FTC and FTA, and a linear combination of expression levels distinguished FTC from FTA with an estimated predictive accuracy of 0.83. Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]). A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules, allowing better treatment decisions and reducing long-term health costs.