Minimally Invasive Follicular Carcinoma Research Articles

Molecular testing in the diagnosis and management of thyroid malignancy: a feasibility study

Abstract Background NHS England’s reorganization of genomic testing has provided an opportunity to explore molecular testing as part of thyroid nodule diagnostics and the routine postoperative histology. Aim Routine molecular testing in an NHS service has not previously been explored. This study aims to evaluate whether (1) there is sufficient material to perform this on an FNAC in cytologically indeterminate nodules (2) what the yield is from indeterminate nodules (3) whether post-operative testing is feasible and (4) whether management is altered. Methods This in an ongoing feasibility study in a UK tertiary institution commenced in January 2021. Data until May in presented. Two groups are enrolled: those with indeterminate pre-operative cytology and those who have undergone thyroidectomy for malignancy. FNAC samples were sent for a routine panel including BRAFv600e, H-K-NRAS and histology for TP53, RET and NTRK in addition. Results Out of 30 patients with indeterminate cytology, molecular testing was requested in eight. The material was insufficient for added molecular testing in six and the panel of mutations tested was negative in two. Thirty-one patients underwent thyroidectomy for malignancy and 11 surgical specimens underwent molecular testing. Mutations were detected in 54.5%(n=6). BRAFv600e mutation was found in four specimens with PTC, whereas NRAS mutation was detected in one Hobnail variant of PTC and one minimal invasive follicular carcinoma. Conclusion Addition of molecular testing to preoperative cytology was shown to require a further FNAC in a majority of cases. In postoperative specimens, molecular testing is feasible but further follow-up is required to determine whether clinical management is altered.

Long-Term Outcome of Patients with TPO Mutations.

Introduction: Thyroid peroxidase (TPO) deficiency is the most common enzymatic defect causing congenital hypothyroidism (CH). We aimed to characterize the long-term outcome of patients with TPO deficiency. Methods: Clinical and genetic data were collected retrospectively. Results: Thirty-three patients with primary CH caused by TPO deficiency were enrolled. The follow-up period was up to 43 years. Over time, 20 patients (61%) developed MNG. Eight patients (24%) underwent thyroidectomy: one of them had minimal invasive follicular thyroid carcinoma. No association was found between elevated lifetime TSH levels and the development of goiter over the years. Conclusions: This cohort represents the largest long-term follow up of patients with TPO deficiency. Our results indicate that elevated TSH alone cannot explain the high rate of goiter occurrence in patients with TPO deficiency, suggesting additional factors in goiter development. The high rate of MNG development and the risk for thyroid carcinoma indicate a need for long-term follow up with annual ultrasound scans.

Ultrasonographic features for differentiating follicular thyroid carcinoma and follicular adenoma

Preoperative differentiation of follicular thyroid carcinoma (FTC) from follicular adenoma (FA) remains an unsolved puzzle. Patients sometimes undergo unnecessary lobectomy for histology confirmation inevitably. In this retrospective study, we propose new gray-scale ultrasonographic (US) features that may help to differentiate FTC from FA. Medical charts and US images of follicular thyroid neoplasms were collected prospectively. Gray-scale US features including conventional parameters adding tubercle-in-nodule and trabecular formation were recorded. The histopathologic diagnosis was FA in 139 and FTC in 49 patients. In patients with FTC, minimally invasive follicular carcinoma (MIFC) was seen in 36 patients and widely invasive follicular carcinoma (WIFC) in 13. The incidences of calcifications (p<0.0001), tubercle-in-nodule signs (p<0.0001), spiculated margins (p=0.014), and trabecular formations (p=0.03) were significantly higher in FTC. Tubercle-in-nodule (p<0.01) and calcification (p<0.001) were independent factors in the differentiation of FTC in multivariate analysis (area under the curve=0.689). US characteristics of tubercle-in-nodule in combination with calcification help to differentiate FTC from FA.

The value of thyroperoxidase as a prognostic factor for differentiated thyroid cancer -- a long-term follow-up study.

BackgroundThyroperoxidase (TPO) is a membrane-bound protein essential for the production of thyroid hormones; because of this, TPO expression may be impaired in selected thyroid diseases. The goal of this study is to analyze TPO immune expression in differentiated thyroid cancer, and to determine whether TPO has any prognostic value.MethodsA total of 139 patients who required surgery due to a thyroid nodule with signs or symptoms suspicious for malignancy during their physical, ultrasound and/or cytology examination were consecutively selected for the study. A study of TPO immunohistochemical expression was carried out on these patients using the MoAb47 monoclonal antibody. In addition, cell proliferation marker Ki67 and tumor suppressor p53 were also measured for comparison.ResultsA total of 139 cases, 43 benign tumors, 42 papillary carcinomas, 38 follicular carcinomas, 8 undifferentiated carcinomas, and 8 sporadic medullary carcinomas were analyzed. The relationship between TPO expression and disease was statistically significant (p <0.001), and decreased with tumor dedifferentiation extent. Increased TPO expression in benign lesions as compared to decreased expression in papillary carcinomas and undifferentiated tumors is outstanding. Differences in TPO expression were observed in minimally invasive follicular carcinoma (MIFC) compared to widely invasive follicular carcinoma (WIFC). TPO expression decreases in undifferentiated malignancies in contrast with p53 and Ki67 expression, which increases in that setting. TPO, p53 and Ki67 expression was significantly related to TNM stage (p <0.001). Survival rate was 72 % after a 20-year follow-up, and 100 % for subjects with higher TPO expression.ConclusionsTPO may be useful in confirming or ruling out benign diseases from differentiated thyroid carcinoma, with the exception of low-risk carcinoma such as MIFC. It could be used as a prognostic factor for differentiated thyroid cancer and patient follow-up, together with other markers.

Minimally invasive follicular carcinoma: predictors of vascular invasion and impact on patterns of care.

Some studies have reported that minimally invasive follicular carcinoma (MIFC) with vascular invasion is associated with compromised prognosis, leading to an ongoing debate regarding extent of surgery for MIFC. Our goal was to identify predictors of vascular invasion and determine its impact on patterns of care. Adult patients with MIFC were culled from the National Cancer Database, 2010-2011, and segregated according to the presence/absence of capsular or vascular invasion. Variables of interest were examined using Chi-square and student's t tests. Multivariate analysis was performed with logistic regression. A total of 617 patients with MIFC were identified: 54% with capsular invasion only and 46% with vascular invasion. Demographic characteristics were similarly distributed between the two groups. Tumor size was larger in patients with vascular invasion (mean = 35.7 vs. 29.2 mm capsular invasion only, p < 0.001); a 2% increase in risk of vascular invasion was observed with each 1 mm increase in size. The rate of total thyroidectomy was similar for MIFCs with vascular invasion compared to capsular invasion only (72.9 vs. 75.1%, p = 0.537). The RAI administration rate was higher in patients with vascular invasion (62.1 vs. 52.6% capsular invasion only, p = 0.017). In multivariate analysis, the presence of vascular invasion was independently associated with increased likelihood of receiving RAI (OR 1.641, p = 0.007). MIFC remains aggressively treated despite current guidelines favoring a more conservative approach. Building consensus around MIFC management is important for standardization of practice patterns and improvement in quality of care.

Immunohistochemical analysis of thyroid follicular neoplasms and BRAF mutation correlation.

The accurate diagnosis of benign and malign thyroid tumors is very important for the clinical management of patients. The distinction of thyroid papillary carcinoma follicular variant and follicular adenoma can be difficult. To investigate the alternative methods like immunohistochemistry and exon 15 in the BRAF gene 1799 T/A mutation analyses for distinguishing thyroid tumors. We applied immunohistochemical markers; CK19, HMWCK, Galectin-3, HBME-1 and Fibronectin and mutant allele-specific PCR amplification technique was used to determine 1799 T/A mutation within the BRAF gene. Formalin-fixed parafin embedded tissues from 45 surgically total resected thyroids, included 26 thyroid papillary carcinoma follicular variant (FV-TPC), 8 Follicular Adenoma (FA), 6 Minimal invasive follicular carcinoma (MIFC) and 5 Follicular Carcinoma (FC). Statistical Analyses Used: Pearson Chi-Square and Kruskal Wallis tests were performed. There was a positive correlation between FV-TPC and HMWCK, CK 19, HBME1, Galectin 3, fibronectin (P < 0.05), but there was no correlation with FV-TPC and BRAF gene mutation (P > 0.05). HBME-1 and CK 19 stained strong and diffuse positive in FV-TPCs but weak and focal in FAs. Our study suggests that morphologic features combined with immunohistochemical panel of HMWCK, CK19, HBME-1, Galectin-3 and fibronectin can help to distinguish benign and malign thyroid neoplasms and FV-TPC from follicular adenomas. BRAF gene 1799 T/A mutation has been non-specific but its detection can be a useful tool combined with immunohistochemistry for diagnosing FV-TPC.

Follicular thyroid cancer: minimally invasive tumours can give rise to metastases

The histological characteristics of follicular thyroid carcinomas (FTCs) are important predictors of prognosis, and lesions can be classified as either minimally invasive follicular carcinoma (MIFC) or widely invasive follicular carcinoma (WIFC) based on histopathological characteristics. There has been controversy surrounding the histological classification of FTC, which can present challenges to clinicians attempting to deliver accurate prognostic information to their patients. The aim of the present study was to examine cases of metastatic FTC for characteristics that may predict aggressive tumour behaviour. The Monash University Endocrine Surgery Unit database was searched for patients with FTC. The histopathology reports were collated for these patients to confirm the diagnosis of FTC, classify patients into MIFC versus WIFC, and examine for key characteristics such as the capsular and/or vascular invasion. The thyroid specimens from patients with metastatic FTC were examined by reviewing pathologists. It was hypothesized that patients with metastatic disease would likely have WIFC as their primary lesion. There were 64 patients with FTC identified during the period of 1997-2009. Of these, 10 patients were found to have metastatic disease. On review of the histopathology, three patients were found to have WIFC,four patients had MIFC and three patients did not have definite features of FTC found in the thyroid gland. Currently accepted histological classification of FTC is inadequate and fails to accurately predict patients with distant metastatic disease and a more aggressive clinical course. It is thus the policy of our unit to recommend total thyroidectomy and radioactive iodine ablation for all patients with FTC.

Minimal Invasive Follicular Thyroid Carcinoma Developed in Dyshormonogenetic Multinodular Goiter Due to Thyroid Peroxidase Gene Mutation.

Background: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has been reported in only one patient harboring mutations in the thyroid peroxidase (TPO) gene. Patient findings: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of L-thyroxine treatment and consequently normal TSH levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland. Summary: Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG. Conclusions: Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma.

A Case of Minimal Invasive Follicular Carcinoma in Childhood

갑상선 암종 중 여포상 암종(follicular carcinoma)은 전 체에서 5~15%를 차지하며, 수술 후 조직병리학적 소견으 로 인접한 갑상선 실질 침범 유무에 따라 미세 침습 여포상 암 종(minimally invasive follicular carcinoma, MIFC)과 광 범위 침습 여포상 암종(widely invasive follicular carcinoma, WIFC)으로 나눌 수 있다. 미세 침습 여포상 암종 을 포함한 갑상선 여포상 암종은 대부분 성인에서 발견되고 소아에서 드물다고 보고되어 있다. 그러나 소아라도 갑상선 부위에 단독 종괴가 만져질 경우 갑상선 암종을 반드시 감별해야 한다. 하지만 소아의 갑상 선 암종은 매우 드물어 15세 이하 악성 종양의 1.5%를 차지 하며, 남아보다는 여아에서 2~3배 많이 발생하고 대부분 7 세 이후에 발생한다. 본 저자들은 2세 소아에서 최소 침습 갑상선 여포상 암종 1예를 경험하여 문헌고찰과 함께 보고하는 바이다. 증 례

Childhood minimally invasive follicular carcinoma: Clinical features and immunohistochemistry analysis

To report on two cases of childhood thyroid minimally invasive follicular carcinoma (MIFC) to highlight the clinical features, laboratory findings and diagnosis of this rare disease. The patients' age, gender, clinical features, laboratory findings, pathology and therapy were reviewed. Immunohistochemistry analysis was performed on the resected masses section. From 2000 to 2008, a total of 15 cases of thyroid cancer were confirmed by pathological analysis, which account for about 2.16% of all malignant solid tumours. They included nine of thyroid papillary carcinoma, two of MIFC and one of undifferentiated thyroid carcinoma. For the two children with MIFC, one was an 8-year-boy and one was a 12-year-old girl. Thyroid mass was found as the primary sign. Imaging findings showed well-defined heterogeneous mass and radionuclide scintigraphy with 99mTc demonstrated small cold nodules in the right lobe of thyroid in two cases. Histopathology confirmed the diagnosis of MIFC. Immunohistochemical staining was positive for thyroglobulin, thyroid transcription factor-1, galectin-3, Hector Battifora mesothelial antigen-1, cytokeratin-AE1/AE3, cytokeratin-19, proliferating cell nuclear antigen and E-cadherin in two cases, and S-100 in one case, while CD56, vimentin and desmin were negative. One case was undertaken lobectomy and the other was undertaken subtotal thyreoidectomy with L-T4 replacement therapy. MIFC is exceedingly rare in children and should be included in the differential diagnosis of thyroid mass. The diagnosis of MIFC depends mainly on the pathological findings.

QPRT: a potential marker for follicular thyroid carcinoma including minimal invasive variant; a gene expression, RNA and immunohistochemical study

BackgroundThe differential diagnosis between follicular thyroid adenoma and minimal invasive follicular thyroid carcinoma is often difficult for several reasons. One major aspect is the lack of typical cytological criteria in well differentiated specimens. New marker molecules, shown by poly- or monoclonal antibodies proved helpful.MethodsWe performed global gene expression analysis of 12 follicular thyroid tumours (4 follicular adenomas, 4 minimal invasive follicular carcinomas and 4 widely invasive follicular carcinomas), followed by immunohistochemical staining of 149 cases. The specificity of the antibody was validated by western blot analysisResultsIn gene expression analysis QPRT was detected as differently expressed between follicular thyroid adenoma and follicular thyroid carcinoma. QPRT protein could be detected by immunohistochemistry in 65% of follicular thyroid carcinomas including minimal invasive variant and only 22% of follicular adenomas.ConclusionConsequently, QPRT is a potential new marker for the immunohistochemical screening of follicular thyroid nodules.

Significance of Expression of Cell Cycle Related Proteins and Apoptosis Related Proteins in Follicular Adenoma and Follicular Carcinoma of Thyroid

Purpose: To explore the role of cell cycle regulators and apoptosis regulators in carcinogenesis of thyroid, the expression of cell cycle related proteins (cyclin D1, Ki-67) and apoptosis related proteins (survivin, caspase 3, bcl-2, p53) were investigated in follicular adenoma and follicular carcinoma of thyroid. Methods: The following formalin-fixed paraffin embedded surgical specimens were immunohistochemically stained by avidin-biotin complex method for cyclin D1, Ki-67, survivin, caspase 3, bcl-2, p53; 15 cases of follicular adenoma (FA), 31 cases of minimally invasive follicular carcinoma (MIFC) and 12 cases of widely invasive follicular carcinoma (WIFC). Results: The overexpression of six gene products in follicular neoplasms of thyroid was noted in varying frequency. Among them, increased Ki-67, caspase 3 index and overexpression of bcl-2 were noted in statistically significant, widely invasive follicular carcinoma than that of follicular adenoma and minimally invasive follicular carcinoma. Conclusion: These results suggest that the overexpression of Ki-67, caspase 3, bcl-2 appear to play an important role during follicular carcinogenesis of thyroid. In addition, the overexpression of these proteins is related to the differentiation of MIFC and WIFC. However, further molecular genetic studies are required to determine the interrelationships between the expression of cell cycle related proteins and apoptosis related proteins. (J Korean Surg Soc 2009;76:7-14)

Thyroid carcinoma in the United Arab Emirates: perspectives and experience of a tertiary care hospital

Although the distribution of thyroid carcinoma in the Arab Gulf States has been described, no previous study has examined the characteristic clinicopathologic features of thyroid carcinoma cases in the United Arab Emirates. The medical records of 135 patients with thyroid carcinoma diagnosed over a 15-year period (1991-2005) at Tawam Hospital, the national referral oncology center in the UAE, were retrospectively studied and the cases classified according to the histologic classification of the World Health Organization (WHO). Seventy-eight patients (58%) were diagnosed before the age of 45 years with an overall peak incidence in the fourth and fifth decades. The female to male ratio was 2.4:1. Eighty-four percent had papillary thyroid carcinoma (PTC), while follicular thyroid carcinoma (FTC), anaplastic thyroid carcinoma and medullary carcinoma comprised 14%, 1.4% and 0.6%, respectively. The conventional classical variant of papillary carcinoma was the most common type. Three-quarters of the papillary carcinomas presented as multinodular goiter, while one-fifth presented as a solitary thyroid nodule. Minimal invasive follicular carcinoma was the most common variant of follicular carcinoma. Thyroid carcinoma in the United Arab Emirates seems to be more common among females and female gender may be a risk factor. Age < 45 years can be considered an important prognostic factor as well as a possible risk factor. PTC predominates the histologic pattern of thyroid carcinoma, which is usually associated with an iodide-sufficient area.

Cell proliferation marker MCM2, but not Ki67, is helpful for distinguishing between minimally invasive follicular carcinoma and follicular adenoma of the thyroid

To compare cell proliferation markers, minichromosome maintenance protein 2 (MCM2) and Ki67, in minimally invasive follicular carcinoma (MIFC) and follicular adenoma (FA) of the thyroid and among MIFCs with different diagnostic criteria. Twenty-two MIFCs and 20 FAs were immunohistochemically stained for MCM2 and Ki67. The MIFCs were subdivided into six Group 1 tumours with both capsular and vascular invasions, seven Group 2 tumours with vascular invasion only and nine Group 3 tumours with capsular invasion only. The MCM2 and Ki67 indices were calculated, counting more than 1000 tumour cells in the most frequently positive areas. In total and Groups 1-3 MIFCs and in FAs, the average MCM2 index was 26.7 +/- 11.0, 28.4 +/- 8.6, 26.3 +/- 14.8, 25.9 +/- 8.4 and 10.7 +/- 4.5, respectively, whereas the average Ki67 index was 2.07 +/- 1.65, 1.93 +/- 2.02, 2.49 +/-1.38, 1.84 +/- 1.5 and 1.78 +/- 0.92, respectively. There was a significant difference in the MCM2 index, but not in the Ki67 index, between each category of MIFCs and FA (P < 0.01). However, neither the MCM2 index nor the Ki67 index showed a statistically significant difference among the subgroups of MIFC. MCM2, but not Ki67, is a helpful marker for differentiating MIFC from FA. The tumour cell proliferative activity supports the histological criteria based on diagnosing MIFC by either capsular or vascular invasion only.

Expression of Galectin-3 in Normal and Malignant Thyroid Tissue by Quantitative PCR and Immunohistochemistry

Galectin-3 has been extensively studied as an immunohistochemical marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses, such as minimal invasive follicular carcinoma. We consequently hypothesized that the quantitative analysis of galectin-3 mRNA rather than the more observer-dependent immunohistological determination might enhance the diagnostic workup of ambiguous thyroid lesions. In the present study, we set out to validate this approach by analyzing concomitantly the expression and production of galectin-3 in benign and malignant thyroid tumors by means of quantitative PCR and immunohistochemistry. Twenty-eight benign and 31 malignant thyroid samples were quantified by real-time PCR for the mRNA levels of galectin-3 and thyroglobulin. Galectin-3 protein expression was examined by immunohistochemistry in 13 benign and 14 malignant thyroid samples. There was a significant increase in galectin-3 at both the mRNA (12/20) and protein levels in papillary cancer (8/8), although the mRNA values overlapped partly with benign lesions. Surprisingly, only a focal and discrete galectin-3 immunoreactivity was seen in follicular cancer (1/5); no augmentation of the mRNA was found. The expression of the thyroid-specific gene thyroglobulin was highly variable in benign and malignant thyroid tissue. These results suggest that the quantitative measurement of galactin-3 mRNA is unlikely to be clinically useful and underscore the need for searching for novel markers for thyroid malignancies.

A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature.

The criteria for minimally invasive (low grade) follicular carcinoma of the thyroid (MI) remain controversial, often resulting in unnecessary treatment. The records of 130 patients with minimally invasive (MI) follicular thyroid carcinoma were retrieved from the files of the Endocrine Tumor Registry of the Armed Forces Institute of Pathology. Ninety-five patients were confirmed to have MI based on the authors' criteria of small-to-medium vessel invasion, capsular invasion of up to full thickness, no parenchymal tumor extension, and no tumor necrosis (patients with oxyphilic tumors were excluded). The remaining 35 patients had tumors that were reclassified as "not low grade" based on large vessel invasion, extension into parenchyma, and tumor necrosis (oxyphilic cases excluded). The MI patients included 67 women and 28 men, ages 20-95 years (average, 42.0 years). Nearly all patients presented with a thyroid mass (n = 90 patients). The mean tumor size was 2.8 cm. Histologic features examined for tumor classification included cellularity, capsule nature, capsular invasion, vascular invasion, extension into parenchyma, cytoplasmic oxyphilia, mitotic activity, and necrosis. All patients were treated with surgical excision. Adjuvant radioactive iodine therapy was performed in 24 patients. Five patients developed recurrent disease: four were alive or had died without evidence of disease after additional treatment (mean, 18.1 years), and one patient died with disease (MI tumor) at 15.1 years. All of the remaining patients were disease free (mean follow-up, 16.5 years). There are reproducible histologic criteria to diagnose patients with MI follicular carcinoma. The overall excellent long term prognosis and a good patient outcome suggests that no additional surgery is necessary.

The Role of Cell Cycle Regulatory Protein, Cyclin D1, in the Progression of Thyroid Cancer

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.