Benign Follicular Thyroid Research Articles

Insulin-Like Growth Factor mRNA Binding Protein 3 (IMP3) is Differentially Expressed in Benign and Malignant Follicular Patterned Thyroid Tumors

Insulin-like growth factor mRNA binding protein 3 (IMP3) is an mRNA-binding protein that regulates transcription of insulin-like growth factor II affecting cell proliferation during embryogenesis. It is highly expressed in carcinomas of the pancreas, stomach, colon, rectum, kidneys, uterine cervix, lung, and ovary. The purpose of our study was to evaluate IMP3 expression in thyroid follicular lesions, to determine whether it has a role in differentiating among these lesions, and to understand their biological relationships. We immunostained 219 thyroid lesions selected from our surgical pathology archives including 14 hyperplastic colloid nodules (CN), 19 Hashimoto's thyroiditis (HT), two Graves disease (GD), ten Hürthle cell adenoma (HCA), 20 follicular adenoma (FA), 37 conventional papillary thyroid carcinoma (PTC), 60 follicular variant of papillary carcinoma (FVPC), 19 Hürthle cell carcinoma (HCC), 32 follicular carcinoma (FC), and six poorly differentiated/anaplastic carcinoma. Immunohistochemistry was performed on formalin-fixed sections using monoclonal antibody to IMP3. Clinicopathological data were also reviewed. In all cases, residual thyroid tissue, CN, HT, GD, HCA, and FA were completely negative for IMP3 staining. Of the 60 FVPC, 23 tumors (38%) were positive for IMP3, with 13 of these (22%) showing very strong staining (3+). Of the 32 FC, 22 tumors (69%) were positive, with seven (22%) showing very strong staining (3+). Furthermore, 33 out of 37 cases (89%) of PTC were negative for IMP3. In all four PTC cases that did stain positive, staining was weak-moderate (1-2+). Similarly, 15 out of 19 cases (79%) of HCC were negative. No significant correlation was found between pathologic tumor characteristics and IMP3 expression in differentiated follicular pattern thyroid carcinoma. With 100% specificity and 69% sensitivity for FC as compared to FA and 100% specificity for FVPC, again compared to FA, IMP3 has the potential to be diagnostically useful in differentiating malignant and benign follicular pattern thyroid lesions. This study also points to a possible common biological relationship between FC and FVPC that requires further investigation.

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.

Adenoid cystic variant of papillary thyroid carcinoma: A case report with fine‐needle aspiration cytology

Diagnostic CytopathologyVolume 36, Issue 1 p. 64-66 Letter to the EditorFree Access Adenoid cystic variant of papillary thyroid carcinoma: A case report with fine-needle aspiration cytology Hüseyin Üstün M.D., M.I.A.C., Hüseyin Üstün M.D., M.I.A.C. Department of Pathology, Ankara Training and Research Hospital, Ankara, TurkeySearch for more papers by this authorFatma Öz Atalay M.D., Corresponding Author Fatma Öz Atalay M.D. [email protected] Department of Pathology, Ankara Training and Research Hospital, Ankara, TurkeyKultur Mah, Atac–2 Sok, No. 72/6, Kizilay, Ankara 06420, TurkeySearch for more papers by this authorCemil Ekinci M.D., Cemil Ekinci M.D. Department of Pathology, Faculty of Medicine, Ankara University, Ankara, TurkeySearch for more papers by this author Hüseyin Üstün M.D., M.I.A.C., Hüseyin Üstün M.D., M.I.A.C. Department of Pathology, Ankara Training and Research Hospital, Ankara, TurkeySearch for more papers by this authorFatma Öz Atalay M.D., Corresponding Author Fatma Öz Atalay M.D. [email protected] Department of Pathology, Ankara Training and Research Hospital, Ankara, TurkeyKultur Mah, Atac–2 Sok, No. 72/6, Kizilay, Ankara 06420, TurkeySearch for more papers by this authorCemil Ekinci M.D., Cemil Ekinci M.D. Department of Pathology, Faculty of Medicine, Ankara University, Ankara, TurkeySearch for more papers by this author First published: 06 December 2007 https://doi.org/10.1002/dc.20716Citations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 DeLellis RA,Lloyd RV,Heitz PU,Eng C. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. p 57– 66. 2 Haji BE,Ahmed MS,Prasad A,Omar MS,Das DK. Papillary thyroid carcinoma with an adenoid cystic pattern. Report of a case with fine-needle aspiration cytology and immunocytochemistry. Diagn Cytopathol 2004; 30: 418– 421. 3 Nguyen GK,Vogelsang PJ,Schumann GB. Follicular carcinoma of thyroid with an adenoid cystic pattern. Acta Cytol 1993; 37: 740– 744. 4 Yamazaki K. Unique follicular carcinoma of the thyroid gland with extracellular deposition of amorphous globular structures mimicking an adenoid cystic pattern. Virchows Arch 2003; 443: 690– 692. 5 El Hag IA,Kollur SM. Benign follicular thyroid lesions versus follicular variant of papillary carcinoma: Differentiation by architectural pattern. Cytopathology 2004; 15: 200– 205. 6 Jogai S,Adesina AO,Temim L,Al-Jassar A,Amanguno HG. Follicular variant of papillary thyroid carcinoma—A cytological study. Cytopathology 2004; 15: 212– 216. 7 Das DK.Malik MK,Scharma P, et al. Papillary thyroid carcinoma and its variants in fine needle aspiration smears. Acta Cytol 2004; 48: 325– 336. 8 Natarjan S,Greaves TS,Raza AS,Cobb CJ. Fine-needle aspiration of an adenoid cystic carcinoma of the larynx mimicking a thyroid mass. Diagn Cytopathol 2004; 30: 115– 118. 9 Van der Wall JE,Becking AG,Snow GB,van der Waal I. Distant metastasis of adenoid cystic carcinoma of salivary glands and the value of diagnostic examinations during follw-up. Head Neck 2002; 24: 779– 783. 10 Highland KE,Finley JL,Neill JSA,Silverman JF. Collagenous spherulosis: Report of a case with diagnosis by fine needle aspiration biopsy with immunocytochemical and ultrastructural observations. Acta Cytol 1993; 37: 3– 9. 11 Jain S,Kumar N,Sodhani P,Gupta S. Cytology of spherulosis of the breast: A diagnostic dilemma—Report of three cases. Cytopathology 2002; 13: 116– 120. 12 Jain S,Gupta S,Kumar N,Sodhani P. Extracellular hyaline material in assosiation with other cytologic features in aspirates from collagenous spherulosis of the breast and adenoid cystic carcinoma of the breast. Acta Cytol 2003; 47: 381– 386. 13 Ogata K,Sakamato G,Sakurai T. Adenoid cystic carcinoma with collagenous spherulosis-like structures in the breast. Report of a case. Pathol Int 2004; 54: 332– 336. Citing Literature Volume36, Issue1January 2008Pages 64-66 ReferencesRelatedInformation

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.

Expression of embryonic stem cell marker OCT4 in human thyroid neoplasia

Current investigations suggested that thyroid carcinoma originate from individual mature thyroid follicular epithelial cells. Here we provide the evidence for a stem cell-associated model of thyroid carcinogenesis. We investigated the expression of the octamer-binding transcription factor-4 (OCT4) in human thyroid tissues. OCT4 is a POU domain–containing transcription factor encoded by Pou5f1 and functions as an important regulator in initial cell fate decisions during mammalian development. We assessed the expression of human OCT4 transcripts in 8 normal and 12 adenoma thyroid tissues, and 12 follicular, 20 papillary and 18 anaplastic thyroid carcinoma (Ca). We also investigated OCT4 expression in seven thyroid cancer cell lines. OCT4 transcripts were detected in most anaplastic carcinoma (80%), but weak or absent in normal thyroid (25%), benign thyroid adenoma (50%), follicular (33%) and papillary (30%) thyroid Ca tissues. Furthermore, OCT4 gene activity was absent in a papillary thyroid Ca cell line (B-CPAP), weak in follicular FTC-238, FTC-236, FTC-133, but strong in anaplastic 8305-C, C643, Hth74 Ca cell lines. The stem cell gene OCT4 may play a direct role and serve as a valuable new biomarker in thyroid carcinogenesis. Future research aims to provide further evidence to our hypothesis that thyroid carcinogenesis includes an involvement of pre-existing stem cells within the adult thyroid gland.

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.

Circulating tumor cells detected by reverse transcription-polymerase chain reaction for carcinoembryonic antigen mRNA: Distinguishing follicular thyroid carcinoma from adenoma

We prospectively tested whether circulating tumor cells could be detected in peripheral blood of patients with thyroid tumors by a reverse transcription-polymerase chain reaction (RT-PCR) to detect carcinoembryonic antigen (CEA) messenger RNA (mRNA). We assayed for CEA mRNA by RT-PCR in peripheral blood sampled before and 2 to 3 weeks after curative surgery for thyroid tumors in 121 patients. Blood samples from 7 patients with chronic thyroiditis and 7 healthy subjects served as controls. No control samples were positive for CEA mRNA by RT-PCR. Of 121 preoperative samples from patients with thyroid tumor, 6 were positive (5.0%). Preoperative frequencies of CEA mRNA positivity in benign tumor, papillary carcinoma, follicular variant papillary carcinoma, minimally invasive follicular carcinoma, and widely invasive follicular carcinoma were 0%, 0%, 0%, 44.4% (4/9), and 50.0% (2/4), respectively. Among positive patients only one, who had widely invasive follicular carcinoma, remained positive after surgery. RT-PCR detection of tumor cells in preoperative blood often can distinguish malignant from benign follicular thyroid tumors.

Benign follicular thyroid lesions versus follicular variant of papillary carcinoma: differentiation by architectural pattern.

Differentiation between benign and malignant follicular lesions is one of the difficult diagnostic areas in thyroid fine needle aspiration (FNA). Nuclear criteria are usually used to distinguish between them. In this study the microarchitectural pattern of common benign follicular lesions, namely nodular hyperplasia (NH) and follicular adenoma (FA) were analysed in comparison with those of follicular variant of papillary carcinoma (FVPC) in order to aid in their differentiation. The FNA smears of histologically proven cases of FVPC, NH and FA were reviewed and compared. The microarchitectural features of FVPC, NH and FA were described. Three cytological features--multi-layered rosettes, branching monolayered sheets and balls of thick pinkish colloid--were exclusively observed in FVPC. Hyperplastic papillae with intact follicles and colloid were frequently seen in NH, 83% and 100%, respectively. Albeit less frequently, they were also noted in FVPC, 25% and 75% of cases, respectively. These overlapping features make the distinction between FVPC and NH sometimes difficult; however, assessing the smears for the specific features of FVPC may help in their differentiation. None of the aforementioned microscopic findings with the exception of the seldom presence of colloid were documented in FA. The crowded clusters of follicular cells were seen both in FA and FVPC; however, they were complex and branching in the latter and round to oval in the former. Finally, smears with good recovery of material are indispensable for the identification of these helpful microarchitectural patterns.

Molecular Analysis of Structural Abnormalities in Papillary Thyroid Carcinoma Genome

Rearrangements of the RET proto-oncogene (RET/PTC) and BRAF gene mutations are the major genetic alterations in the etiopathogenesis of papillary thyroid carcinoma (PTC). We have analyzed a series of 118 benign and malignant follicular cell-derived thyroid tumors for RET/PTC rearrangements and BRAF gene mutations. Oncogenic rearrangements of RET proto-oncogene was revealed by semiquantitative RT-PCR of simultaneously generated fragments corresponding to tyrosine kinase (TK) and extracellular RET domains. The clear quantitative shift toward the TK fragment is indicative for the presence of RET rearrangements. The overall frequency of RET/PTC rearrangements in PTC was 14% (12 of 85), including 7 RET/PTC1, 2 RET/PTC3, 1 deltaRFP/RET and 2 apparently uncharacterized rearrangements. The most common T1796A transversion in BRAF gene was detected in 55 of 91 PTC (60%) using mutant-allele-specific PCR. We also identified two additional mutations: the substitution G1753A (E585K) and a case of 12-bp deletion in BRAF exon 15. Moreover, there was no overlap between PTC harboring BRAF and RET/PTC mutations, which altogether were present in 75.8% of cases (69 of 91). Taken together, our observations are consistent with the notion that BRAF mutations appear to be an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. Neither RET/PTC rearrangements nor BRAF muta-tions were detected in any of 3 follicular thyroid carcinomas, 11 follicular adenomas and 13 nodular goiters. The high prevalence of BRAF mutations and RET/PTC rearrangements in PTCs and the specificity of these alterations to PTC make them potentially important markers for the preoperative tumor diagnosis.

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.

A KRAB zinc finger protein gene is the potential target of 19q13 translocation in benign thyroid tumors

In an attempt to identify the target gene of specific translocations involving chromosomal band 19q13 in benign follicular thyroid tumors, we have used two cell lines derived from benign thyroid tumors showing translocations with 19q13 breakpoints for fluorescence in situ hybridization mapping studies with cosmid and PAC clones located in a 400-kbp region. The breakpoints of the chromosome 19 abnormalities mapped within a 140-kb segment covered by a single PAC clone. Sequencing of part of this PAC clone allowed us to establish the cDNA sequence and the genomic structure of a candidate gene located in close vicinity to the breakpoints. The gene that we tentatively refer to as RITA (rearranged in thyroid adenomas) belongs to the KRAB zinc finger protein coding genes. From our results we have concluded that in the two cell lines investigated the breaks have occurred either within the 5' untranslated region of RITA or in its close 5' vicinity. By Northern blot analyses two transcripts of about 4.7 kbp and 5 kbp were detected in normal thyroid tissue as well as in other normal tissues tested. An additional 2.1-kbp transcript was found only in testicular tissue. In contrast to all normal tissues, both cell lines with 19q aberrations expressed larger transcripts of approximately 5.5 kbp and 6.2 kbp. From the close vicinity to the breakpoint region, the expression patterns of the gene, and its type, we consider RITA a strong candidate target gene of the specific 19q aberrations in benign thyroid tumors.

Occupational and Environmental Determinants for Benign Thyroid Disease and Follicular Thyroid Cancer.

Occupational and environmental determinants of benign thyroid disease and follicular thyroid cancer were evaluated in a series of cases in 1977-1987. Of the cases initially diagnosed as follicular thyroid cancer, only 31 remained after a reclassification, whereas 44 were found to be benign thyroid disease. Both series were compared with 387 randomly selected population controls. Occupational solvent exposure was strongly associated with benign thyroid disease (odds ratio, OR, 2.8; 95% confidence interval, 95% CI, 0.9-9.0 for women and OR 18.9; 95% CI 2.2-161 for men). Eight of the nine men found to have benign disease had been exposed to solvents, and six of them to trichloroethylene. For both types of cases, a private well at the birth address increased the risk, OR 2.0; 95% CI 0.9-4.0 and OR 3.0; 95% CI 1.2-7.2, respectively, whereas the risk was lower for those living in coastal areas. Less fish and shellfish in the diet increased the risk for malignant thyroid disease only. Although based on small numbers, the study indicates etiologic roles of occupational and environmental factors for both conditions studied. The influences of occupation and diet differ, however, for the two outcomes.

Occupational and Environmental Determinants for Benign Thyroid Disease and Follicular Thyroid Cancer

Occupational and Environmental Determinants for Benign Thyroid Disease and Follicular Thyroid Cancer