cyclin-d1 and Carcinoma--Papillary

Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by exophytic proliferation of neoplastic epithelial cells with fibrovascular stalks in bile duct lumen, mucin hypersecretion, and considerable dilatation or multilocular changes of the affected bile ducts. A mucin-producing bile duct tumor is an IPNB with excessive mucin production and clinical symptoms. Herein, the phenotypes as well as the tumorigenesis and progression of IPNB are reviewed with immunohistochemical assistance. The tumors are subdivided into three phenotypes: pancreatobiliary, intestinal, and gastric. About half of IPNB cases are of the pancreatobiliary type, and the remaining half are of the intestinal type. Aberrant expression of CDX2 with MUC2 and CK20 is related to the development of intestinal metaplasia. Inactivation of P16INK4a and nuclear expression of beta-catenin are related to the development of IPNB. Decreased expression of membranous beta-catenin and E-cadherin and aberrant expression of MMP-7 and -9 and of MUC1 are related to invasion of IPNB with tubular adenocarcinoma, whereas MUC2 is involved in the invasion of IPNB with mucinous carcinoma. IPNB can be regarded as a counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, particularly the main duct type. More comparative studies between IPNB and pancreatic IPMN are recommended for further analysis of these papillary neoplasms.

Topics: Adenocarcinoma, Mucinous; beta Catenin; Bile Duct Neoplasms; Cadherins; Carcinoma, Ductal; Carcinoma, Papillary; CDX2 Transcription Factor; Cholangiocarcinoma; Cyclin D1; Disease Progression; Homeodomain Proteins; Humans; Immunohistochemistry; Keratin-20; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Mucin-1; Mucin-2; Mucins; Neoplasm Invasiveness; Pancreatic Neoplasms; Phenotype

Cyclin D1 expression was examined in benign and differentiated malignant thyroid tumors to determine diagnostic utility and correlation with tumor type, size, and nodal status; 29 follicular adenomas (FA), 23 follicular carcinomas (FCA) and 43 papillary thyroid carcinomas (PTC) (22 with and 21 without nodal metastases) were stained. PTCs included 27 classical (PTCC) and 16 follicular variants (PTCFV). A statistically significant association was found between tumor type and cyclin D1 staining, distribution, and intensity. There were fewer cyclin D1-positive FAs than PTCs (52% vs. 88% respectively; P<0.001) and stain distribution was greater in PTC than FA (P=0.032). More PTCs were positive than FCAs (88% vs. 61%, respectively; P=0.013). All significant comparisons remained significant after adjusting for tumor size. FA did not differ from FCA in staining/intensity. There were fewer cyclin D1-positive FAs than PTCC (52% vs. 89%, respectively; P=0.003) and PTCFV (52% vs. 88%, respectively; P=0.023). FCA also differed significantly from PTCC in staining (61% vs. 89%, respectively; P=0.044) and intensity (P=0.024). In terms of cyclin D1 intensity, FA had significantly less intense staining than PTCC (P=0.004). No significant associations were found between PTC nodal status and any cyclin D1 characteristic. In conclusion, cyclin D1 shows heterogeneity in distribution and intensity in benign and malignant thyroid tumors, which disqualifies it as a primary diagnostic marker in these tumors; however, it may be helpful in distinguishing FA from PTC, especially PTCFV. Its expression by thyroid tumors suggests a role in tumor development and may be an early event in thyroid neoplasia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Papillary; Child; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Metastasis; Thyroid Neoplasms

With the continuous discovery of new borderline thyroid lesions and benign and malignant "gray areas", coupled with the limitations of traditional immune indicators, the differential diagnosis of papillary thyroid carcinoma (PTC) has become more difficult. Cyclin D1 and P21 are cell cycle regulators involved in the occurrence and metastasis of multiple tumors, including PTC, but their specific functions are unclear.. In our study, immunohistochemical staining was used to explore the expression of Cyclin D1 and P21 in PTC, paracancerous tissue, follicular adenoma (FA) and papillary thyroid hyperplasia. In addition, their relationship with the clinicopathological features of PTC and their differential diagnostic value in distinguishing between intralymph node PTC metastases and intralymph node ectopic thyroid tissue were studied.. Among 200 primary PTC lesions, Cyclin D1 and P21 were found to be expressed in 186 (93.00%) and 177 (88.50%), respectively, and their expression levels were significantly higher in PTC tissue than in adjacent tissue, FA tissue and papillary thyroid hyperplasia tissue (P < 0.05). The expression levels of Cyclin D1 and P21 were positively correlated with tumor size and lymph node metastasis (P < 0.05) but not with sex, age, number of tumor lesions, histological subtype, chronic lymphocytic thyroiditis or TNM stage (P < 0.05). The expression levels of Cyclin D1 and P21 were significantly correlated (P < 0.05). The positivity rates of Cyclin D1 and P21 in intralymph node PTC metastases were 97.96% (48/49) and 89.80% (44/49), respectively, which were significantly higher than those in intralymph node ectopic thyroid tissue (P < 0.05). The sensitivity (Se) and negative predictive value (NPV) of Cyclin D1 and P21 detection alone or in combination were higher than those of the combined detection of the classical antibody markers CK19, HBME-1 and Galectin-3. Besides, the Se, Sp, PPV and NPV of Cyclin D1 and P21 in differentiating intralymph node PTC metastases and intralymph node ectopic thyroid tissue were higher.. The results of our study show that Cyclin D1 and P21 are highly sensitive and specific markers for the diagnosis of PTC that are superior to traditional classical antibodies. And, these two markers are of great value in the differential diagnosis of intralymph node PTC metastases and intralymph node ectopic thyroid tissue.

Topics: Adenoma; Biomarkers, Tumor; Carcinoma, Papillary; Cyclin D1; Diagnosis, Differential; Humans; Hyperplasia; Thyroid Cancer, Papillary; Thyroid Dysgenesis; Thyroid Neoplasms

To investigate the expression of several immunohistochemical (IHC) markers and their predictive ability for the recurrence-free and progression-free survival of papillary urothelial bladder cancer (UBC) pTa/pT1 G2 (WHO 1973) compared to classical anatomo-clinical variables using a multidimensional analysis.. A population-based cohort of 213 primary stage UBC (pTa/pT1) G2 (WHO 1973) was evaluated by classic anatomopathological variables and characterized by immunohistochemistry (23 IHC markers, representative of different oncogenic pathways). The most important variables as a predictor of recurrence-free and progression-free survival were selected using multidimensional statistical models, such as random survival forests and least absolute shrinkage and selection operator (. Recurrence and progression-free survival of the previously selected variables were also calculated.. Mean follow-up was 58 ± 33.5 months. Recurrence and progression rates were 54.5% (n = 116) and 17,4% (n = 37), respectively. The most influential variables in the low recurrence-free survival were in order: number of resected tumors, high expression of Ki67 (>10%), Cyclin D1 (>10%), and low cytoplasmic staining of p16INK4a. Regarding low progression-free survival, the most important variables were Ki67 (>15%), multicentric tumor arrangement and Survivin nuclear expression (>20%). Kaplan-Meier and cox-regression model analyses showed that the variables selected by multidimensional models were able to discriminate the clinical outcome.. Ki67 index is the most useful IHC marker, since it can improve the prediction of both recurrence and progression-free survival in papillary UBC pTa/pT1 G2 (WHO 1973). There are other markers, whose utility is specific to recurrence-free survival, such as Cyclin D1 and p16INK4a or in progression-free survival, such as Survivin.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Papillary; Cohort Studies; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Follow-Up Studies; Humans; Ki-67 Antigen; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Predictive Value of Tests; Survival Rate; Survivin; Urinary Bladder Neoplasms

Th e aim of the study was to determine the influence of RET, p27 and cyclin D1\ on regional lymph node metastases in papillary microcarcinoma. The analysis included 70 patients\ with papillary thyroid microcarcinoma that underwent surgery at Split University Hospital Center\ between 1999 and 2001. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded\ tissue by the RET, p27 and cyclin D1 antibodies. Quantification was based on the intensity and\ distribution of nuclear staining, dividing tumors into those that showed expression (expressors) and\ those that showed no expression (non-expressors). Univariate analysis using χ²-test and Fisher exact\ test was performed with the level of statistical significance set at p<0.05. There was no statistically\ significant difference in the incidence of metastases according to the expression or non-expression of\ RET mutation (χ²-test: p=0.459; Fisher exact test: p=0.672). Among 25 cases with cyclin D1 expression,\ 6 had metastases, whereas only 2 of 45 cases with no cyclin D expression had metastases (χ²-test:\ p=0.014; Fisher exact test: p=0.021), indicating that the expression of cyclin D1 is not crucial for the\ development of metastases in lymph nodes. In contrast, analysis of p27 expression showed it to be\ significantly associated with lymph node metastasis because 3 of 45 patients with p27 expression had\ metastases, indicating a statistically significant correlation between p27 expression and lymph node\ metastases (χ²-test: p=0.093; Fisher exact test: p=0.124). This study confirmed the importance of the\ evaluation of RET, p27 and cyclin D1 expression and demonstrated the validity of their application in\ the assessment of microcarcinoma behavior.

Topics: Carcinoma, Papillary; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms

Recent evidences indicates that hydroxytyrosol, one of the main olive oil phenols, possess antitumor effects because of its pro-oxidant properties and the capacity to inhibit proliferation and to promote apoptosis in several tumor cell lines, although most of the results were obtained for breast and digestive systems cancers.. In this study, we evaluated the activities of hydroxytyrosol against papillary (TPC-1, FB-2) and follicular (WRO) thyroid cancer cell lines.. Cellular viability revealed that high doses of hydroxytyrosol reduced cancer cells viability concomitantly with a reduction of cyclin D1 expression and an up-regulation of cell cycle key modulator p21 levels. In the same experimental conditions, Annexin V-PI staining and DNA laddering revealed that hydroxytyrosol exerts proapoptotic effects on papillary and follicular cancer cells. Furthermore, by Western blot analysis, we observed that hydroxytyrosol treatment reduced thyroid cancer cells viability by promoting apoptotic cell death via intrinsic pathway.. Collectively, our results demonstrated for the first time that in thyroid cancer cells hydroxytyrosol promoted apoptosis at higher doses with respect to other cancer cells lines. Therefore, further studies will reveal the mechanisms by which thyroid cancer cells are more resistant to the proapoptotic effect exerted by hydroxytyrosol as well as the potential application as novel target therapeutic in thyroid cancer.

Topics: Adenocarcinoma, Follicular; Antioxidants; Apoptosis; Blotting, Western; Carcinoma, Papillary; Cell Proliferation; Cyclin D1; Dose-Response Relationship, Drug; Humans; Phenylethyl Alcohol; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Neoplasms; Tumor Cells, Cultured

The objective of this study was to compare the protein expression profile between well-differentiated (papillary) and undifferentiated (anaplastic) thyroid carcinoma in Tunisian patients.. This first Tunisian retrospective study concerned data of 38 thyroid cancer cases (19 papillary carcinoma PTC and 19 anaplastic carcinoma ATC) collected at Salah Azaiez Institute of Tunisia. Immunohistochemistry was used to evaluate tumor expression of different molecular markers (p53, Ki67, E-cadherin, cyclin D1, bcl2, S100 and Her-2). The molecular expression was correlated with the clinicopathological characteristics of the tumors.. There were 6 differentially expressed markers when comparing anaplastic thyroid carcinoma ATC with papillary thyroid carcinoma PTC. Expression of p53 and Ki67 were significantly increased in 16 and 18 ATC cases respectively, the Ki67 expression was lost in PTC. Cyclin D1, E-cadherin, bcl2 and S100 were overexpressed in PTC tumors; however, they were significantly decreased in ATC. The last marker, Her-2 was expressed in one case of PTC only.. Our results, similar with findings of other ethnic groups, showed alteration in expression of molecular markers associated with tumor dedifferentiation, indicating loss of cell cycle control with increased proliferative activity in ATC carcinoma. These data support the hypothesis that ATC may derive from dedifferentiation of preexisting PTC tumor.

Topics: Adult; Aged; Biomarkers, Tumor; Cadherins; Carcinoma, Papillary; Cyclin D1; Female; Humans; Ki-67 Antigen; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Receptor, ErbB-2; Retrospective Studies; S100 Proteins; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Suppressor Protein p53; Tunisia

o-Nitroanisole is an intermediate in the manufacture of azo dyes. In a National Toxicology Program stop-exposure study,o-nitroanisole induced hyperplasia, papillomas, and papillary carcinomas in the urinary bladder of Fischer 344/N rats.o-Nitroanisole was investigated since occupational or environmental exposure to aniline and azo dyes is a risk factor for urinary bladder cancer in humans. The current study describes the morphology of urinary bladder neoplasms seen in rats with respect to those observed in humans. This study also evaluated immunohistochemical expression of the cell cycle-related proteins cyclin D1 and p53 and the differentiation markers cytokeratin 20 and uroplakin III in hyperplastic (n= 11) and neoplastic (n= 6 papillomas,n= 11 carcinomas) lesions of the urinary bladder epithelium from rats treated with o-nitroanisole and in normal (n= 6) urinary bladders from untreated rats. The tumors observed were more similar to the papillary type rather than the muscle-invasive type of urinary bladder cancer in humans. The preneoplastic and neoplastic lesions observed suggest progression from hyperplasia to papilloma to papillary carcinoma. With neoplastic progression (hyperplasia to papilloma to carcinoma), cyclin D1 immunoreactivity progressively increased in intensity, percentage of cells staining, and distribution. Overexpression of p53 was not found. Cytokeratin 20 staining decreased in superficial cells, while uroplakin III staining increased in intermediate and basal cells with progression from hyperplasia to carcinoma. The results are consistent with increased cell cycle dysregulation or proliferation (cyclin D1), decreased differentiation (cytokeratin 20), and abnormal differentiation (uroplakin III) as lesions progress toward malignancy.

Topics: Animals; Anisoles; Biomarkers, Tumor; Carcinoma, Papillary; Cyclin D1; Disease Models, Animal; Female; Humans; Hyperplasia; Immunohistochemistry; Keratin-20; Male; Papilloma; Precancerous Conditions; Rats; Rats, Inbred F344; Tumor Suppressor Protein p53; Urinary Bladder; Urinary Bladder Neoplasms; Uroplakin III

Recent functional genomic studies revealed that the oncogenic activity of focally amplified lncRNA on chromosome 1 (FAL1, ENSG00000228126) contributes to tumor growth by p21 repression in human cancers. However, the expression of FAL1 was not investigated in papillary thyroid cancer (PTC). We aimed to determine if FAL1 was up-regulated in PTC compared to paired contralateral normal thyroid tissues, and to investigate the potential targets of this lncRNA and its clinicopathological significance in PTC. We analyzed FAL1 and p21 expression levels in 100 PTC samples and matched normal thyroid tissue by qRT-PCR. Using lncRNA microarray data from the Gene Expression Omnibus (accession no. GSE61763), we explored potential targets of FAL1 by Gene Set Enrichment Analysis, followed by verification by qRT-PCR in our PTC samples. A cross-sectional observational study was conducted to investigate the relationship between patients' clinicopathological features and FAL1 expression. FAL1 expression was significantly higher in PTC than in paired normal thyroid tissues (paired t test, P < 0.001). p21 mRNA expression was also increased, not decreased, in PTC, and had no correlation with FAL1 expression (r = 0.0897, P = 0.4002). Gene Set Enrichment Analysis, using publicly available microarray data, indicated that a gene set related to the cell cycle, including E2F transcription factors 1 and 2, and cyclin D1, was coordinately enriched among samples with high FAL1 expression. A volcano plot showed that E2F1, E2F2, and VEGFA mRNAs were increased in the high FAL1 samples. In clinicopathological analyses, multifocality was more frequently observed in PTC patients with high FAL1 (P = 0.018). Multivariate analysis showed that high FAL1 expression increased the risk of multifocality (after adjustment for clinical variables, OR = 4.019, CI = 1.041-11.020, P = 0.043). FAL1 may have a role in cell-cycle progression and may be associated with aggressive tumor behavior in PTC.

Topics: Adult; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cross-Sectional Studies; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; E2F1 Transcription Factor; E2F2 Transcription Factor; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; RNA, Long Noncoding; RNA, Messenger; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Up-Regulation; Vascular Endothelial Growth Factor A

Proliferation and apoptosis are opposing processes by which the cell numbers are kept in a delicate balance, essential for tissue homeostasis, whereas uncontrolled growth of cells is a hallmark of cancer. Papillary thyroid cancer (PTC) is the commonest type of thyroid cancer, with some PTC following an indolent course, whereas the other ones are more aggressive.. To evaluate respective contribution of proliferation and apoptosis in the tumorigenesis of PTC by automated analysis.. We investigated the immunolabeling of phosphorylated histone H3 (pHH3), cyclin D1, active caspase-3, and bcl-2 in thirteen cases each of metastatic PTC, follicular variant of PTC (FVPTC), papillary microcarcinoma (PMC) and well differentiated tumor of uncertain malignant potential (WDT-UMP). FVPTC cases comprised seven encapsulated and six unencapsulated cases.. Proliferation, as assessed by pHH3 and cyclin D1 immunolabeling, was increased in all PTC variants, including the putative precursor lesion WDT-UMP, compared to normal thyroid tissue. pHH3 was immunolabeled in more cells of metastatic PTC than of PMC and of encapsulated FVPTC. Surprisingly, metastatic PTC and unencapsulated FVPTC also demonstrated more cleaved caspase-3 immunolabeled cells than the other types. In contrast, increased expression of bcl-2 protein was seen in normal thyroid areas, encapsulated FVPTC and PMC as compared to metastatic PTC. Metastatic PTC shows higher proliferation than other types of PTC but unexpectedly also higher apoptotic levels. Similar results were also seen with unencapsulated FVPTC, thus suggesting that unencapsulated FVPTC has a potential for adverse outcome. Bcl-2 was immunolabeled in a low percentage of cells in WDT-UMP.. The expression of the proliferative protein pHH3 together with the apoptotic marker cleaved caspase-3 may indicate an aggressive behaviour of PTC and loss of apoptosis inhibition by bcl-2 protein can further amplify the role of these proteins in tumor progression. Both cyclin D1 and bcl-2 could prove to be interesting markers of PTC precursor lesions. Automated/digital image quantification approach helps in refining the diagnostic accuracy.

Topics: Apoptosis; Automation; Biomarkers; Carcinoma, Papillary; Caspase 3; Cell Division; Cyclin D1; Histones; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Signal Processing, Computer-Assisted; Specimen Handling; Staining and Labeling; Thyroid Neoplasms

The diagnosis of intraductal papillary lesions of the breast on core biopsy remains challenging in pathology, with most patients requiring formal surgical excision for a definitive diagnosis. The aim of this study was to determine whether a representative panel of proliferative cell cycle immunohistochemical markers (cyclin A2, cyclin B1 and cyclin D1) could improve the specificity of pathological diagnosis of these lesions.. A series of 68 surgically excised intraductal papillary lesion cases were retrospectively selected, and immunohistochemistry for cyclin A2, cyclin B1 and cyclin D1 was performed.. Cyclin B1 (OR 1.80, 95% CI 1.01 to 3.2, p=0.046) and cyclin D1 (OR 1.13, 95% CI 1.05 to 1.22, p=0.002) expression was independently associated with a diagnosis of malignancy in papillary lesions, although expression was frequently heterogeneous and only focal. Cyclin A2 expression (OR 0.76, 95% CI 0.41 to 1.4, p=0.38) was not associated with a malignant diagnosis in multivariable logistic regression models. All three cyclins displayed high sensitivity (80%-95%) for a diagnosis of malignancy, although cyclin B1 showed a superior specificity of 72.7% compared with the low specificity of cyclins A2 and D1.. Our study has identified for the first time that the expression of key cell cycle markers differs between benign and malignant papillary breast lesions and identified changes to the mitotic marker, cyclin B1, as particularly significant. However, given the low level and heterogeneous nature of expression of these markers, there remains a significant risk of undersampling in core biopsies and thus they are unlikely to be useful in routine clinical practice.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Papillary; Cell Cycle; Cell Proliferation; Cyclin A2; Cyclin B1; Cyclin D1; Female; Humans; Immunohistochemistry; Logistic Models; Middle Aged; Multivariate Analysis; Odds Ratio; Papilloma, Intraductal; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Factors

Encapsulated follicular tumours with equivocal papillary thyroid carcinoma (PTC) type nuclear features continue to remain a challenge despite the recent attempts to classify these borderline lesions. The term 'well differentiated tumour of uncertain malignant potential (WDT-UMP)' was introduced to classify these tumours. The present study aimed to evaluate the role of a cell cycle regulator like cyclin D1 in these tumours along with assessment of other well established PTC markers like galectin-3, HBME-1, CK19.. Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from a histological review of 510 cases. In addition, 13 cases of a subset of follicular adenomatoid nodules with focal areas showing nuclear features characteristic of PTC, identified as WDT-UMP, were also analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK19 and the proliferation markers Ki67 and cyclin D1 was performed. Lesions were analyzed for cyclin D1 gene amplification by fluorescent in-situ hybridization.. All WDT-UMP lesions showed immunolabelling of cyclin D1, Ki67; 11/ 13 cases showed immunolabelling of CK19; 10/13 cases showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling of galectin-3. Surrounding benign adenomatoid areas showed no to faint focal staining in all thirteen cases of cyclin D1, HBME-1 and galectin-3. A low rate of cyclin D1 gene amplification was identified in a significant proportion of cells in the WDT-UMP lesions as compared to surrounding benign adenomatoid areas.. Increased expression of cyclin D1 and amplification of its gene along with immunolabelling of HBME-1 in WDT-UMP lesions showing cytological features of papillary thyroid carcinoma within follicular adenomatoid nodules suggest that these areas could correspond to a precursor lesion of follicular variant of PTC. Overexpression of cyclin D1, associated with the amplification of the gene suggests that these WDT-UMP lesions are an intermediate between the benign and malignant groups making this group of lesions a reliable precursor of FVPTC.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1851820807142117.

Topics: Adenocarcinoma, Follicular; Adenoma; Adolescent; Adult; Biomarkers, Tumor; Biopsy; Blood Proteins; Carcinoma; Carcinoma, Papillary; Cell Differentiation; Cyclin D1; Female; Galectin 3; Galectins; Gene Amplification; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Keratin-19; Ki-67 Antigen; Male; Middle Aged; Predictive Value of Tests; Thyroid Cancer, Papillary; Thyroid Neoplasms; Up-Regulation

Several studies have demonstrated that thyroid hormone T3 promotes cancer cell growth, even though the molecular mechanism involved in such processes still needs to be elucidated. In this study we demonstrated that T3 induced proliferation in papillary thyroid carcinoma cell lines concomitantly with an up-regulation of cyclin D1 expression, that is a critical mitogen-regulated cell-cycle control element. Our data revealed that T3 enhanced the recruitment of the TRβ1/Oct-1 complex on Octamer-transcription factor-1 site within cyclin D1 promoter, leading to its transactivation. In addition, silencing of TRβ1 or Oct-1 expression by RNA interference reversed both increased cell proliferation and up-regulation of cyclin D1, underlying the important role of both transcriptional factors in mediating these effects. Finally, T3-induced increase in cell growth was abrogated after knocking down cyclin D1 expression. All these findings highlight a new molecular mechanism by which T3 promotes thyroid cancer cell growth.

Topics: Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Octamer Transcription Factor-1; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Thyroid Cancer, Papillary; Thyroid Hormone Receptors beta; Thyroid Neoplasms; Triiodothyronine; Up-Regulation

Cullin 1 (Cul1) is a rigid scaffold protein of a major class of E3 ubiquitin ligase, also known as the Skp1/cullin1/F-box (SCF) complex, which is involved in cell-cycle progression. The aberrant expression of Cul1 is involved in the dysfunction of SCF E3 ligase. Previous studies have revealed an association between increased Cul1 expression and tumor progression and poor outcome in several different tumors. We constructed a tissue microarray containing 103 papillary carcinoma tissues of the thyroid and 66 normal thyroid tissues. Cul1 expression and Cyclin D1 expression were evaluated by immunohistochemistry staining, and the relationship between their expression and clinicopathological parameters were analyzed. Cytoplasmic expression of Cul1 was correlated with tumor occurrence (p < 0.001), N stage (p = 0.027), and Cyclin D1 expression (p < 0.001). Cyclin D1 expression showed a correlation with tumor occurrence (p < 0.001) and T stage (p = 0.009). On the other hand, nuclear expression of Cul1 showed a negative correlation with tumor occurrence (p < 0.001) and Cyclin D1 expression (p < 0.001). Cytoplasmic Cul1 expression was associated with tumor development and higher nodal metastasis status, supporting the idea that the SCF complex is involved in cell-cycle regulation and promotes cell proliferation. Nuclear expression of Cul1 showed inverse relationship between tumor aggressiveness factors. Our data suggest that the expression site of Cul1 may affect the function of the SFC complex and play a role in tumor progression.

Topics: Adult; Aged; Carcinoma, Papillary; Cullin Proteins; Cyclin D1; Female; Humans; Male; Middle Aged; Thyroid Neoplasms; Tissue Array Analysis; Young Adult

Cyclin D1 is an important positive regulator of the G1/S phase of the cell cycle. We investigated the association between the CCND1 G870A polymorphism and susceptibility to papillary thyroid cancer in Turkish people. This study covered 102 patients with papillary thyroid cancer and 174 healthy controls. CCND1 genotyping was determined by the PCR-RFLP method. We found that the A allele frequency was higher in the cases than in the controls (p=0.042). On stratification analysis, papillary thyroid cancer risk was significantly elevated in individuals older than 45 years with the A allele (OR=1.91, 95% CI, 1.09-3.35, p=0.024) and in females with the A allele (OR=1.73, 95% CI, 1.06-2.84, p=0.029), compared to the G allele. According to the subject age, there was an increased papillary thyroid cancer risk for the individuals older than 45 years with the AA genotype (OR=2.28, 95% CI, 1.02-5.13, p=0.046) compared to the AG+GG combined genotypes. In conclusion, it is suggested that the CCND1 G870A polymorphism may contribute to the susceptibility to papillary thyroid cancer, especially in those who were older subjects (45 ≤ years old) and female, in the Turkish population.

Topics: Adult; Age Factors; Asian People; Carcinoma; Carcinoma, Papillary; Case-Control Studies; Cyclin D1; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Sex Factors; Thyroid Cancer, Papillary; Thyroid Neoplasms; Turkey

Smad4 is a key mediator of the transforming growth factor-β (TGF-β) superfamily that is involved in the control of cell proliferation and differentiation. We recently demonstrated that a Smad4 mutation, Smad4 C324Y, isolated from nodal metastases of papillary thyroid carcinoma, causes an increase of TGF-β signaling, responsible for the acquisition of transformed phenotype and invasive behaviour in thyroid cells stably expressing this mutation. In this paper, we demonstrate that the stable expression of Smad4 C324Y mutation in FRTL-5 cells is responsible for TSH-independent growth ability. Our data show that the Smad4 C324Y mutation interacts with P-Smad3 more strongly than Smad4 wt, already in basal condition; this interaction is responsible for TGF-β signaling and PKA activation that, in turn, determines an increased phosphorylation of CREB, necessary for the mitogenic actions of TSH. The expression of cyclin D1 also increases in all cells overexpressing the Smad4 C324Y mutation. All together, these data demonstrate that Smad4 C324Y mutation, interacting with the PKA pathway, gives cells the ability to proliferate independently from TSH.

Topics: Carcinoma; Carcinoma, Papillary; Cell Differentiation; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cyclin D1; Humans; Mutation; Phosphorylation; Smad3 Protein; Smad4 Protein; Thyroglobulin; Thyroid Cancer, Papillary; Thyroid Gland; Thyroid Neoplasms; Thyrotropin; Transforming Growth Factor beta

Papillary thyroid microcarcinoma generally carries an excellent prognosis, and fatal cases are becoming increasingly rare. Their pathologic and molecular features, however, remain largely unknown. We describe 3 cases of papillary thyroid microcarcinoma that, despite surgical and radioiodine treatment, recurred, metastasized, and eventually caused the death of the patients. In addition to morphology, immunohistochemical (cyclin D1 and p53) and molecular analyses (BRAF [v-raf Murine sarcoma viral oncogene homolog B1], KRAS [V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog], HRAS [v-Ha-ras Harvey rat sarcoma viral oncogene homolog], NRAS [neuroblastoma RAS viral oncogene homolog], and PIK3CA [phosphoinositide-3-kinase, catalytic, alpha polypeptide]) were performed. Interestingly, all 3 cases presented with massive lymph node metastases that showed morphological evidence of "tumor progression" (tall cell features, poorly differentiated areas, and high-grade cytologic features). Cyclin D1 was consistently immunoreactive in both primary and metastatic site, whereas p53 was negative. BRAF V600E was absent in both sites, and KRAS, HRAS, NRAS, and PIK3CA were consistently wild type. These data suggest that, in cases of metastatic papillary thyroid microcarcinoma, an accurate morphologic analysis of the metastatic deposits could contribute to a more accurate prediction of tumor behavior.

Topics: Aged; Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Combined Modality Therapy; Cyclin D1; Disease Progression; DNA Mutational Analysis; Fatal Outcome; Female; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy

To evaluate the expression levels of cyclin D1 in breast papillomas and papillary carcinomas, and to analyze the types of cells that co-express cyclin D1 with cytokeratin 5/6 (CK 5/6) or with cytokeratin 8/18(CK 8/18).. Fifty-nine cases of papillary lesions including 36 papillomas and 23 intracystic papillary carcinomas were examined. Cyclin D1, CK 5/6 and CK 8/18 expression levels were evaluated by double immunostaining.. Cyclin D1 is highly expressed in papillary carcinomas (27.54% ± 15.43%) compared with papillomas (8.81% ± 8.41%, p < 0.01). Cyclin D1 is predominantly expressed in cytokeratin 8/18- expressing cells, rather than in cytokeratin 5/6-expressing cells, regardless of the type of lesion. In papillomas, cyclin D1 exhibited a mean 11.42% (11.42% ± 10.17%) co-expression rate with cytokeratin 8/18 compared with a mean 2.50% (2.50% ± 3.24%) co-expression rate with cytokeratin 5/6 (p < 0.01). In papillary carcinomas, cyclin D1 exhibited a mean 34.74% (34.74% ± 16.32%) co-expression rate with cytokeratin 8/18 compared with a co-expression rate of 0.70% (0.70% ± 0.93%) with cytokeratin 5/6 (p < 0.01).. The increase in cyclin D1 suggests an association of cyclin D1 staining with papillary carcinomas. Although cyclin D1 is an effective marker for the differential diagnosis of other papillary lesions, it cannot be used to distinguish between papilloma and papillary carcinoma lesions because its expression occurs in both lesions. Our results show that cyclin D1 and CK 5/6 staining could be used in concert to distinguish between the diagnosis of papilloma (cyclin D1 < 4.20%, CK 5/6 positive) or papillary carcinoma (cyclin D1 > 37.00%, CK 5/6 negative). In addition, our data suggest that cyclin D1 is expressed only in the cancer stem or progenitor cells that co-immunostained with CK 8/18 in papillary carcinomas, and predominantly with CK 8/18 in the papillomas.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7299340558756848.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Papillary; Cyclin D1; Female; Humans; Immunohistochemistry; Keratin-18; Keratin-5; Keratin-6; Keratin-8; Middle Aged; Papilloma; Young Adult

The aim of this study was to evaluate the expressions of oncoproteins and to correlate the results with clinicopathologic parameters in papillary thyroid carcinoma (PTC). Papillary thyroid cancer (PTC) is the most common form and accounts for about 80% of all thyroid cancers. Although PTC generally has a good prognosis, some patients suffer from local recurrence and/or distant metastasis. Oncogenes have reported to be related not only in carcinogenesis but also in tumor prognosis, tumor type, differentiation and site of tumor in epithelial malignant tumors such as thyroid, breast, ovarian, and stomach cancer. This study was planned retrospectively and was performed in 87 patients (47 PTC, 40 benign lesions). The data of clinicopathologic parameters and tissue samples were collected from the archives. Sections stained with H&E were evaluated for each case and after confirming the diagnosis of PTC, oncoprotein expressions were determined by immunohistochemical analysis. The differences of oncoprotein expressions in PTC compared with control group were statistically significant. Cyclin D1 and p53 expressions were significantly increased in PTC. The expressions of bcl-2 and c-erbB-2 in PTC were found as increased, but the correlation between these proteins and poor prognostic parameters were not significant. We suggest that increased expressions of cyclin D1 and p53 could be used as prognostic factors in patients with PTC.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Cyclin D1; Female; Follow-Up Studies; Genes, erbB; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neoplasm Staging; Oncogene Proteins; Prognosis; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Thyroid Neoplasms; Tumor Suppressor Protein p53; Young Adult

We examined the expression of cyclin D1 in conjunction with β-catenin and the phosphorylated inactive form of glycogen synthase kinase 3β (GSK-3β) in benign, nonneoplastic thyroid tissue as well as papillary thyroid carcinoma primary tumors and nodal metastases. We aim to unravel the regulation of cyclin D1 and determine if this cell cycle protein is a useful biomarker for metastatic disease. It is clear that expression of cyclin D1 (P < .0001), β-catenin (P < .0001), and inactive form of GSK-3β (P < .0001) are significantly higher in papillary thyroid carcinoma primary tumors than in corresponding benign, nonneoplastic tissue thyroid specimens. Interestingly, β-catenin and cyclin D1 expressions in papillary thyroid carcinoma are correlated (P = .025), implying that β-catenin is a factor driving higher levels of cyclin D1 consistent with previous cell models linking Wnt/β-catenin signaling and cyclin D1 expression. Conversely, inactive form of GSK-3β expression does not correlate with cyclin D1 (P = .52) or β-catenin expression (P = .54). We also did not observe any relationship between tumor size and marker expression. Comparing papillary thyroid carcinoma primary tumors with or without nodal metastases, we did not see any differences in expression of inactive form of GSK-3β (P = .95), β-catenin (P = .14), or cyclin D1 (P = .46). However, in papillary thyroid carcinoma lymph node specimens, the up-regulation of cyclin D1 (P = .0083) was highly significant compared with primary tumors. pGSK-3β and β-catenin expression did not vary between primary tumors and nodal specimens. In conclusion, we have demonstrated that expression of cyclin D1 is linked to nodal metastases and that cyclin D1 levels are regulated by Wnt/β-catenin signaling. GSK pathway-mediated regulation of β-catenin or cyclin D1 expression does not appear operative in papillary thyroid carcinoma.

Topics: beta Catenin; Biomarkers, Tumor; Carcinoma, Papillary; Cyclin D1; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lymphatic Metastasis; Male; Middle Aged; Phosphorylation; Thyroid Gland; Thyroid Neoplasms; Wnt Signaling Pathway

CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease- and γ-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or γ-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of γ-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma.

Topics: Amyloid Precursor Protein Secretases; Animals; Carcinoma, Papillary; Cell Line, Tumor; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Cyclin D1; Humans; Hyaluronan Receptors; Metalloproteases; Oncogenes; Phosphorylation; Promoter Regions, Genetic; Proteolysis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-ret; Rats; Signal Transduction; Thyroid Neoplasms; Transcription, Genetic

Increased incidence of papillary thyroid carcinoma (PTC) is observed as a consequence of radiation exposure in connection to the Chornobyl nuclear plant accident in 1986. In this study, we report a cohort of adult Ukrainian patients diagnosed with PTC from 2004 to 2008 following exposure at the age of 18 years or younger.. In total, 70 patients were identified and clinically characterized. The common BRAF 1799T>A mutation was assessed by pyrosequencing, the RET/PTC1 and RET/PTC3 (NCOA4) rearrangements by RT-PCR, and the expression of Ki-67 (MIB-1 index), BCL2, cyclin A, and cyclin D1 by immunohistochemistry.. In total, 46/70 (66%) cases carried a BRAF mutation and/or a RET/PTC rearrangement. A BRAF mutation was detected in 26 tumors, RET/PTC1 in 20 cases, and RET/PTC3 in four cases. In four of these cases, BRAF mutation and RET/PTC rearrangement were coexisting. The BRAF mutation was underrepresented among PTCs with accompanying chronic lymphocytic thyroiditis (CLT) compared with PTCs without this feature (12 vs 44%). MIB-1 proliferation index determined by double staining with leukocyte common antigen was low (mean 0.8%; range 0.05-4.5%). Moreover, increased expression of cyclin A was observed in PTCs with a tumor size >2 cm compared with PTCs ≤2 cm (1.2 vs 0.6%). BCL2 and cyclin D1 showed frequent expression but without associations to clinical characteristics or amplification of the CCND1 locus.. Our results suggest that this cohort has frequent BRAF mutation, RET/PTC1 rearrangement, and low proliferation index. Furthermore, BRAF 1799T>A was underrepresented in PTCs with CLT, and cyclin A expression was associated with increased PTC tumor size.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Papillary; Chernobyl Nuclear Accident; Cohort Studies; Cyclin A; Cyclin D1; Female; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Ki-67 Antigen; Male; Middle Aged; Mutation; Neoplasms, Radiation-Induced; Nuclear Receptor Coactivators; Patched Receptors; Phenotype; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-ret; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Sequence Analysis, DNA; Thyroid Neoplasms; Ukraine; Up-Regulation; USSR

Marfan syndrome (MFS) is an autosomal dominant hereditary disorder of connective tissue associated with perturbations in transforming growth factor β (TGF-β) biology, most often due to mutations in FBN1 gene that encodes fibrillin-1. To our knowledge, there is no known association of MFS with thyroid carcinoma. We report a 46-year-old man with known history of MFS who developed an unusual histological variant of papillary thyroid carcinoma. The tumor exhibited a widely invasive florid papillary growth pattern with prominent long villous fronds. Immunohistochemical and molecular analysis revealed a BRAF(V600E) mutation, evidence of aggressive biomarker expression (positivity for HBME-1, cytokeratin 19, galectin-3 and cyclin D1, and loss of p27), and changes associated with TGF-β-related epithelial-to-mesenchymal transition with active phospho-SMAD signaling. We introduce a unique histological pattern of papillary thyroid carcinoma that is associated with MFS. The combination of BRAF(V600E) mutation in the setting of altered TGF-β signaling and weak connective tissue integrity associated with MFS may cooperate and possibly be responsible to form this unique villous morphology with epithelial-to-mesenchymal transition and invasive growth.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Cyclin D1; Epithelial-Mesenchymal Transition; Galectin 3; Humans; Keratin-19; Male; Marfan Syndrome; Middle Aged; Mutation; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins B-raf; Signal Transduction; Smad Proteins; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transforming Growth Factor beta

Well-differentiated thyroid cancer (WDTC) is the most frequent form of endocrine neoplasia. One of the main challenges in the management of this disease is distinguishing low-risk patients who can be treated by surgical resection of the lesion from those with a high likelihood of recurrence who need a more extensive approach, including total thyroidectomy and radioiodine ablation.. A tissue microarray (TMA) comprising 410 cases of WDTC was constructed with risk estimates for the following features: extrathyroidal extension, lymph node metastases, and vascular invasion. The variables examined were morphologic classification, candidate genetic, and proteomic biomarkers.. BRAF (Raf kinase type B) mutant carriers showed increased risk of developing invasion compared with wild-type (WT) cases. However, when classified morphologically, classic papillary thyroid carcinomas (PTC) showed much higher risk estimates for invasive features compared with follicular variant PTCs (FVPTC); within these morphologic subgroups, BRAF mutational status did not provide independent risk estimates. Staining intensities for membranous galectin-3 (Gal3), HBME-1, and CK19 and nuclear Gal3 were statistically validated as markers of aggressive behavior. Estrogen receptor beta (ERβ) was overexpressed in lesions with invasive behavior. The utility of these biomarkers remained statistically significant in the FVPTC. In contrast, a different set of biomarkers proved effective in classic PTC where upregulation of cyclin D1, loss of p27, and overexpression of ERβ were associated with invasive behavior.. Different proteomic signatures validate the distinction of classic and FVPTC and provide a practical clinical mechanism to predict the thyroid cancer behavior and stratify patients for clinical management.

Topics: Biomarkers, Tumor; Carcinoma, Papillary; Cyclin D1; DNA Mutational Analysis; Estrogen Receptor beta; Female; Galectin 3; Genotype; Humans; Immunohistochemistry; Keratin-19; Male; Mutation; Prognosis; Proteome; Proteomics; Proto-Oncogene Proteins B-raf; Risk Factors; Thyroid Neoplasms; Thyroidectomy; Tissue Array Analysis

To evaluate the expression of cell-cycle regulators in papillary thyroid carcinoma in relation to lymph node metastatic features, and to determine whether immunohistochemical staining of cell-cycle markers can predict lymph node metastasis.. Cross-sectional study of prior surgical specimens.. Academic tertiary referral center.. We reviewed the clinical records of patients who had undergone surgery for thyroid cancer and follicular adenoma between January 2005 and May 2008 at our clinic. Among these cases, 92 patients, comprising 28 patients with follicular adenoma, 32 with papillary thyroid carcinoma without lymph node metastasis, and 32 with papillary thyroid carcinoma with lymph node metastasis, were selected randomly. Formalin-fixed, paraffin-embedded tissues from the 92 patients were immunohistochemically stained for cyclin D1, cyclin E, p27(kip1), and p57(kip2), and protein expression levels were quantified and compared among the groups.. Tumor specimens from the papillary thyroid carcinoma group had significantly higher expression levels of cyclin D1 and cyclin E, and cytoplasmic expression of p57(kip2) than the other two groups (P < 0.05). In particular, all malignant cases expressed cyclin D1, and cytoplasmic p57(kip2) was expressed only in malignant cases. Furthermore, differences in the grade of cyclin D1 expression according to lymph node metastasis were statistically significant (P < 0.05).. Our results suggest that immunohistochemistry of certain cell-cycle regulators may be helpful in the diagnosis of papillary thyroid carcinoma, and that cyclin D1 in particular may be a useful marker for evaluating lymph node metastasis.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Papillary; Cross-Sectional Studies; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Lymphatic Metastasis; Male; Middle Aged; Retrospective Studies; Thyroid Neoplasms

RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the beta-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3beta (GSK3beta) phosphorylation, thereby reducing GSK3beta-mediated NH(2)-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with beta-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)beta-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3beta complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a beta-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing beta-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells. Silencing of beta-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of beta-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on beta-catenin to stimulate cell proliferation.

Topics: beta Catenin; Carcinoma, Papillary; Cell Nucleus; Cell Proliferation; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Cyclin D1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Phosphotyrosine; Promoter Regions, Genetic; Proto-Oncogene Proteins c-ret; Signal Transduction; TCF Transcription Factors; Thyroid Neoplasms

Solid pseudopapillary tumor (SPT) of the pancreas is very rare. This study was performed to analyze the expression of Wnt signal target genes (matrix metalloproteinase-7 [MMP-7], cyclin-D1, and c-myc) and Ki-67 in resected SPTs to determine their clinicopathologic characteristics according to their expression.. From January 1995 to December 2005, 23 patients underwent pancreatic resections for SPT of the pancreas. Among 23 formalin-fixed, paraffin-embedded tissues, 12 were evaluated as a pilot study. Immunohistochemistry was performed using various detection and antigen retrieval methods to detect MMP-7, cyclin-D1, c-myc, and Ki-67. The expression of Wnt target genes was correlated with clinicopathologic features of the patients.. Solid pseudopapillary tumors of the pancreas always showed cytoplasmic/nuclear accumulation of [beta]-catenin, frequent expression of cyclin-D1, and low proliferation index. MMP-7, cyclin-D1, c-myc, and Ki-67 were not correlated with microscopic features suggesting malignant potential (P > 0.05). Tumor size was closely related to microscopic features of malignant potential and apparently has an inverse relationship with the expression of cyclin-D1 and Ki-67 (P < 0.05).. Low proliferative index and associated MMP-7 expression may cause an unpredictable clinical course in this tumor. Subtle changes in the intracellular environment, not pathologic (morphologic) changes, may elucidate the unpredictable clinical course of this tumor.

Topics: Adolescent; Adult; beta Catenin; Carcinoma, Papillary; Cyclin D1; Female; Gene Expression; Genes, myc; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Matrix Metalloproteinase 7; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Wnt Proteins

To observe clinical and pathological features of pancreatic solid-pseudopapillary tumor (SPPT), and to find some useful immunohistochemical methods for its differential diagnosis.. The clinical features of 14 SPPT patients were obtained. Each case underwent microscopic observation and immunohistochemical staining. The primary antibodies were CgA, Syn, E-cadherin, beta-catenin and Cyclin D1. These results were compared with 5 pancreatic well-differentiated tumors and well-differentiated carcinomas (WET/WEC).. SPPT mainly involved young women, and the head of pancreas was the commonest location. Tumors were always in solid and cystic gross appearance. Although the tumor's borderlines seemed clear, focal infiltrations could often be identified. The histological features of SPPT were similar in some aspects to those of WET/WEC, especially the solid pattern of WET/WEC. Both of them could express CgA and Syn. But all SPPTs lost E-cadherin membranous signals, and even had some nuclear signals(5/14), while all WET/WECs remained the same staining pattern with normal pancreas cells. beta-catenin positive signals in SPPTs were located both in nuclei and plasmas. WET/WECs' positive signals were all in membranes and plasmas, but negative ones in nuclei. Perinuclear dot-like signals could also be seen in the majority cells, which were similar to normal islet cells' staining pattern. SPPTs' nuclear positive rates of Cyclin D1 were usually more than 70% (12/14). WET/WECs' rates were all lower than 30%.. Comprehensive analysis of patients' clinical, pathological features and immunohistochemistry results, including E-cadherin, beta-catenin and Cyclin D1, was helpful to the diagnosis of SPPT and its differential diagnosis of WET/WEC.

Topics: Adult; beta Catenin; Cadherins; Carcinoma, Papillary; Cyclin D1; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Male; Middle Aged; Pancreatic Neoplasms; Young Adult

In order to define more effective predictive markers for clinical management and prognosis, we evaluated the expression of cyclin D1 and survivin in large papillary thyroid carcinoma (LPTC) and microcarcinoma (PTM). Sixty-seven patients operated for papillary carcinoma (36 of which with PTM) were considered. Immunochemistry for cyclin D1 and survivin was performed in samples from tumor mass and nodal metastases. There were not significant differences between LPTC and PTM as to patients personal data, TNM or MACIS staging, nodal invasion and multifocality, while capsular invasion was significantly more frequent in LPTC. Cyclin D1 and survivin were expressed at a very high rate and almost to the same extent in LPTC and PTM, both in tumoral mass and in nodal metastases. Survivin showed only cytoplasmic expression. Cyclin D1 and survivin over-expression are probably early events in tumorigenesis of thyroid papillary carcinoma but their full role in the process of tumor progression and their clinical value are still to be investigated.

Topics: Adolescent; Adult; Aged; Carcinoma, Papillary; Child; Child, Preschool; Cyclin D1; Female; Humans; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Lymphatic Metastasis; Male; Microtubule-Associated Proteins; Middle Aged; Neoplasm Proteins; Survivin; Thyroid Neoplasms

To determine the prognostic value of cell cycle regulators cyclin D1 and p27 for papillary thyroid carcinomas.. Analysis included 180 patients with papillary thyroid carcinoma who underwent surgery at Split University Hospital Center between 1999 and 2001. Clinical data were obtained from clinical charts and histopathology reports. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue by antibody p27 and cyclin D1. Quantification was based on the intensity and distribution of nuclear staining.. Univariate analysis showed that sex (P=0.019) and capsular invasion (P=0.010) were significant predictors of lymph node metastases, whereas age (P=0.96), histopathological variant (P=0.075), size (P=0.556) and multifocality (P=0.131) were not. Univariate analysis also showed that overexpression of cyclin D1 (P<0.001) and underexpression of p27 (P<0.001) predicted lymph node metastases in papillary thyroid carcinomas. There was a significant correlation between cyclin D1 (P=0.024) and p27 (P=0.029) expression in two prognostic groups of low and high risk. Low risk group was cyclin D1 negative and p27 positive, while high risk group was cyclin D1 positive and p27 negative. Multivariate analysis confirmed that sex (P=0.041), capsular invasion (P=0.027), and p27 (P<0.001) were strong independent predictors of lymph node metastases in the high-risk group.. Immunohistochemical analysis of p27 expression may be a valuable tool for identifying risk of lymph node metastases and more aggressive behavior of papillary thyroid carcinoma.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Papillary; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Predictive Value of Tests; Prognosis; Risk Assessment; Thyroid Neoplasms

Differentiated thyroid cancer (DTC) generally has a favorable outcome, but some patients develop local recurrence and/or distant metastases and ultimately die of their disease. Molecular markers that accurately predict tumor behavior are lacking. This study's aim was to ascertain the role of cell cycle regulators in predicting malignant histology and tumor behavior in DTC.. Tissue microarrays consisting of 100 benign and 105 malignant thyroid lesions, plus 24 lymph node samples, were stained for p16, p21, p27, p53, p57, p63, cyclin D1, cyclin E, and mdm2. Statistical analysis was used to compare the expression of the markers in benign versus DTC lesions and correlate their expression with clinicopathologic characteristics.. p16, p21, cyclin D1, and cyclin E showed significantly (P < .001) increased expression in DTCs compared with benign thyroid lesions (54.7% vs. 5%, 71.7% vs. 38%, 87.1% vs. 45.7%, and 72.3% vs. 37.4%, respectively). There was no significant difference in expression between benign lesions and DTC for the remaining markers. p16 expression correlated significantly with extrathyroidal tumor extension (P = .02) and the presence of cancer in lymph nodes (P = .03). A total of 73% vs. 45% of the cancers of patients with and without lymph node involvement, respectively, stained positive for p16 (P = .01).. There is a statistically significant difference in the expression of p16, p21, cyclin D1, and cyclin E between DTCs and benign thyroid lesions, and p16 expression correlates with clinicopathologic variables predicting poor outcomes for DTC. These results suggest that evaluation of cell cycle derangement in thyroid tumors may serve as a useful tool for both DTC diagnosis and prognosis.

Topics: Adenoma; Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Papillary; Cell Cycle; Cell Cycle Proteins; Cell Differentiation; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Female; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Male; Medical Records; Middle Aged; Oxyphil Cells; Prognosis; Prospective Studies; Thyroid Neoplasms; Tissue Array Analysis; Tissue Fixation; Tumor Suppressor Proteins

This study addressed the immunohistochemical expression of MUC1 in papillary thyroid carcinoma (PTC) of different histotypes, sizes, and morphological features of aggressiveness, and its correlation with the overexpression of cyclin D1, a target molecule of the Wnt pathway. MUC1 expression was examined in a total of 209 PTCs. Cytoplasmic MUC1 expression was elevated in the tall, columnar cell and oncocytic variants (100%), Warthin-like (78%), and conventional PTCs (61%), and in papillary microcarcinoma (PMC) with the conventional growth pattern (52%). On the contrary, it was low in the follicular variant (27%) of PTC and PMCs with follicular architecture (13%). Cytoplasmic MUC1 accumulation did not associate with any clinicopathological features except peritumoral lymphoid infiltration in PTCs and in PMCs with the conventional growth pattern. MUC1 staining correlated with cyclin D1 overexpression in conventional PTCs and PMCs and PMCs with follicular architecture. The results demonstrate that MUC1 expression varies broadly in different histological variants of PTC, being the lowest in tumors with follicular structure. In general, it does not prove to be a prognosticator of PTC aggressiveness. A high correlation between MUC1 and cyclin D1 implies MUC1 involvement in the Wnt cascade functioning in a large subset of human PTCs and PMCs.

Topics: Adult; Carcinoma, Papillary; Cyclin D1; Cytoplasm; Female; Genetic Markers; Humans; Immunohistochemistry; Male; Middle Aged; Mucin-1; Neoplasm Invasiveness; Paraffin Embedding; Prognosis; Thyroid Neoplasms

Cell cycle progression is facilitated by cyclin dependent kinases (CDKs) that are activated by cyclins, including Cyclin D1 and inhibited by CDK inhibitors. Evidence of the involvement of cyclin gene alterations and over expression of various cyclins in human cancer is growing. The role of Cyclin D1 in malignant progression of papillary carcinomas of the thyroid has yet to be established. We therefore studied the expression of Cyclin D1 protein in thyroid carcinomas of young Kuwaiti patients (36 cases of conventional papillary thyroid carcinoma, 12 cases of its follicular variant, one case of tall cell thyroid carcinoma and one case of medullary carcinoma) using immunohistochemistry. In 23 patients (46%) circumscribed areas of cells were detected that showed a distinct to strong nuclear staining for immunoreactive Cyclin D1 whereas the remaining bulk of the carcinoma cells were negative or only showed a slight cytoplasmic staining. None of the tested clinical or path histological parameters showed a statistically significant correlation with the focal immunostaining. This does not rule out that the detected foci with positive nuclear Cyclin D1 immunostaining are areas where a progressive transformation to a more malignant phenotype occurs which eventually leading to lymph node and distant metastases.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Carcinoma, Papillary; Child; Child, Preschool; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Thyroid Gland; Thyroid Neoplasms

The BRAF mutation may influence the expression patterns of molecular markers that are related to the development and progression of thyroid cancer.. The objective of the study was to investigate the effects of the BRAF V600E mutation on expression of galectin-3, cyclooxygenase-2, cyclin D1, p53, and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC).. One hundred sixty-three PTC and 28 nodular hyperplasia patients were selected retrospectively. The presence of the BRAF V600E mutation and the level of expression of the molecular markers were determined.. Of 161 PTC patients, 102 patients (63.4%) were BRAF V600E(+), and these cases had significantly larger tumor sizes (P = 0.01), compared with V600E(-) cases (n = 59, 36.6%). Although PTC tissues had higher expression levels of the selected molecular markers than nodular hyperplasia tissues, expression levels of several molecular markers in BRAF V600E(+) PTC were not significantly different from those of BRAF V600E(-) PTC. But VEGF was significantly up-regulated in BRAF V600E(+) PTC, compared with BRAF V600E(-) PTC. VEGF expression levels were strongly positively correlated to tumor size (P < 0.001), extrathyroidal invasion (P = 0.02), and tumor stage (P = 0.04). Multivariate analysis clearly showed that VEGF expression was up-regulated in BRAF V600E(+) PTC (odds ratio 2.5, confidence interval 1.1-5.6; P = 0.03).. BRAF V600E(+) PTC tended to have larger tumor volumes and higher expression of VEGF. The level of VEGF expression was closely correlated with tumor size, extrathyroidal invasion, and stage. The relatively high levels of VEGF expression may be related to poorer clinical outcomes and recurrences in BRAF V600E(+) PTC.

Topics: Adult; Carcinoma, Papillary; Cyclin D1; Cyclooxygenase 2; DNA, Neoplasm; Female; Galectin 3; Humans; Immunohistochemistry; Male; Middle Aged; Point Mutation; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Retrospective Studies; Thyroid Neoplasms; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A

Solid pseudopapillary tumor (SPT) is an unusual pancreatic neoplasm of low malignant potential that most frequently occurs in young women. The tumor is indolent, with long patient survival, even in the presence of extension into adjacent organs and metastases. Histologically, it is a solid and cystic tumor with a prominent vascular network and degenerative pseudopapillae formation. Despite its distinctive morphology and cytological features, its histogenesis is unclear. Herein, we report a case of solid pseudopapillary tumor in a 41-year-old female in which the tumor cells immunohistochemically and ultrastructurally suggest a centroacinar cell origin. The tumor cells and the normal centroacinar cells stained positive for alpha-antitrypsin (alpha-AT), CD10, cyclin D1 and NSE. Ultrastructural examination shows similarities in nuclear shape, nucleoli location and cytoplasmic contents between neoplastic cells and normal centroacinar cells of the pancreas. Based on both immunohistochemical and ultrastructural features, we propose that the centroacinar cell is the origin of SPT.

Topics: Adult; alpha 1-Antitrypsin; Carcinoma, Papillary; Cyclin D1; Female; Humans; Islets of Langerhans; Neprilysin; Pancreatic Neoplasms; Phosphopyruvate Hydratase

Genetic screening studies suggest that genetic changes underlie progression from well differentiated to anaplastic thyroid cancers. The aim of this study is to determine to what extent cell cycle/apoptosis regulators contribute to cancer progression.. Tissue microarrarys (TMAs) were constructed from well-differentiated papillary thyroid carcinoma (WDPTC; n = 41), poorly differentiated thyroid carcinoma (PDTC; n = 43), and anaplastic thyroid carcinoma (ATC; n = 22). TMAs were immunostained for 7 different cell cycle/apoptosis-related genes (p53, Ki-67, bcl-2, mdm-2, cyclin D1, p21, and p27).. p53 (0%, 12%, 32%) and Ki-67 (5%, 49%, 82%) were expressed with increasing frequency, and bcl-2 (68%, 42%, 0%) and p21 (40%, 7%, 0%) with decreasing frequency in WDPTC to PDTC and ATC, respectively (P < .001). Interestingly, mdm-2 (54%, 5%, 0%) showed decreased expression along the progression axis (P < .001). p27 and cyclin D1 were expressed in <15% of cases, with a trend toward decreasing expression from WDPTC to PDTC to ATC.. These data confirm the presence of increasing genetic complexity with progressive dedifferentiation in thyroid cancer, with aberrant tumor suppressor activity and increased proliferative activity being most prevalent in ATC. The data also confirm the intermediate position of PDTC in the classification scheme of thyroid carcinomas.

Topics: Apoptosis; Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Cell Cycle; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease Progression; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Ki-67 Antigen; Microarray Analysis; Predictive Value of Tests; Prognosis; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Thyroid Neoplasms; Tumor Suppressor Protein p53

Proteins controlling cell growth, differentiation, apoptosis, and oncogenic stress are often deregulated in tumor cells. However, whether such deregulations affect tumor behavior remains poorly understood in many tumor types. We recently showed that the urothelium-specific expression of activated H-ras and SV40 T antigen in transgenic mice produced two distinctive types of tumors strongly resembling the human superficial papillary tumors and carcinoma in situ of the bladder, respectively. Here we assessed the expression of a key set of cell cycle regulators in these mouse tumors and in a new transgenic line expressing a cyclin D1 oncogene in the urothelium. We found that urothelia of the wild-type and cyclin D1 transgenic mice exhibited a profile of cell cycle regulators found in quiescent (G(0)) cells, indicating that urothelium overexpressing the cyclin D1 (an 8-fold increase) is reminiscent of normal urothelium and remains slow-cycling. Low-grade superficial papillary tumors induced by activated H-ras had no detectable Rb family proteins (Rb, p107, and p130) and late cell cycle cyclins and kinases (cyclin A, E, and CDK1), but had increased level of p16, p53, and MDM2. These data suggest that the inactivation of the Rb pathway plays an important role in H-ras-induced superficial papillary tumors and that oncogenic H-ras can induce a compensatory activation of alternative tumor suppressor pathways. In contrast, carcinoma in situ of the bladder induced by SV40 T antigen had increased expression of cell cycle regulators mainly active in post-G(1) phases. The fact that phenotypically different bladder tumors exhibit different patterns of cell cycle regulators may explain why these tumors have different propensity to progress to invasive tumors. Our results indicate that the transgenic mouse models can be used not only for studying tumorigenesis but also for evaluating therapeutic strategies that target specific cell cycle regulators.

Topics: Animals; Antigens, Polyomavirus Transforming; Carcinoma, Papillary; Cell Cycle; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Genes, ras; Hyperplasia; Mice; Mice, Transgenic; Proliferating Cell Nuclear Antigen; Retinoblastoma Protein; Tumor Suppressor Proteins; Urinary Bladder Neoplasms; Urothelium

In a recent epidemiological screening study in an autopsy series, we found a high prevalence of microcarcinomas (MCs) (21/443 = 4.74%). We found no iodine intake-, gender-, or age-dependent differences in the prevalence of MCs. The results suggest a different and benign behavior of MCs compared to clinical cancer. The role of cyclin D1 overexpression in the pathogenesis of thyroid tumors is not known clearly; however, overexpression of this protein was reported in well-differentiated papillary cancers and in incidentally found metastasizing MCs. To date, cyclin D1 expression has not been investigated in autopsy-derived thyroid MCs. Eight MCs were available for immunostaining and comparison with 15 clinically detected papillary thyroid cancers. Fourteen out of 15 clinical carcinomas expressed cyclin D1 (93.3%), while in the MCs this ratio was 1 out of 8 (12.5%) (p = 0.0001). The only cyclin D1-positive MC was multifocal (both lobes of the gland were affected). We concluded that the benign behavior of most autopsy-derived MCs may be associated with the lack of cyclin D1 overexpression.

Topics: Adult; Aged; Carcinoma, Papillary; Cyclin D1; Female; Histocytochemistry; Humans; Hungary; Male; Middle Aged; Prevalence; Thyroid Neoplasms

We recently demonstrated that papillary microcarcinomas with preoperatively detectable node metastasis in the lateral compartment on ultrasonography (clinically apparent metastasis) show worse postoperative relapse-free survival than those with no metastasis or metastasis that could not be detected preoperatively, but was confirmed by pathological examination after surgery (occult metastasis). In this study, we investigated difference in the aggressive characteristics of microcarcinoma of this type from various perspectives.. We immunohistochemically examined the expression of cell proliferating markers, Ki-67, cyclin D1, p27, and retinoblastoma gene product (pRb), apoptotic markers, single-strand DNA (ssDNA), and metastatic suppressor, kangai-1 (KAI-1) for 19 microcarcinoma patients with clinically apparent metastasis, 14 patents with occult metastasis, and 22 patients without metastasis.. Cases of clinically apparent metastasis showed increased cyclin D1 expression together with decreased p27 expression and higher levels of pRb and Ki-67 expression. Furthermore, ssDNA expression was higher and bcl-2 expression was lower in these cases, while KAI-1 expression was significantly reduced. There was no significant difference in the expression of these proteins between cases demonstrating no and occult metastases.. These findings suggest that cases of clinically apparent metastasis show significantly higher growth based on cell proliferating activity, apoptosis, and expression of metastatic suppressor than those demonstrating no or occult metastases.

Topics: Adult; Aged; Antigens, CD; Apoptosis; Biomarkers, Tumor; Carcinoma, Papillary; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Disease-Free Survival; DNA, Single-Stranded; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kangai-1 Protein; Ki-67 Antigen; Lymph Nodes; Lymphatic Metastasis; Male; Membrane Glycoproteins; Middle Aged; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein; Thyroid Neoplasms; Treatment Outcome; Tumor Suppressor Proteins; Ultrasonography

Currently we lack biochemical or molecular markers that predict recurrence and metastases in thyroid cancer. Recent studies in a number of other human malignancies indicate that expression and/or subcellular localization of certain cell cycle regulators has prognostic utility. We have investigated the expression of cyclins D1 and E and of cyclin-dependent kinase inhibitor's p21 and p27 in papillary thyroid cancer (PTC) and correlated this with clinical/histological stage at diagnosis and with clinical outcome. PTCs were compared to normal thyroid, adenomas, and undifferentiated thyroid cancers (UTCs). Our studies indicate that PTCs and UTCs demonstrate low nuclear expression of cyclin E and p27, allowing a clear distinction between adenomas and these carcinomas (p < 0.004). A pattern of low nuclear expression of all four markers was observed in stage IV PTCs and UTCs, while stage I PTCs had low D1 and E accompanied by high p21 or p27. Expression of cytoplasmic cyclin D1 was significantly lower in stage IV PTCs and UTCs than in stage I-III PTC's (p

Topics: Adolescent; Adult; Aged; Carcinoma; Carcinoma, Papillary; Cell Cycle; Cell Cycle Proteins; Cell Nucleus; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Retrospective Studies; Thyroid Neoplasms; Tissue Fixation; Tumor Suppressor Proteins

Cyclin D1 is a target molecule transcriptionally activated by aberrant beta-catenin in Wnt signalling. Thyroid papillary microcarcinoma (PMC) may be considered a precursor of papillary thyroid cancer (PTC). Ki67 is widely used as a proliferation marker. The aim of this study was to determine whether cyclin D1 overexpression is involved in early thyroid carcinogenesis.. Thirty-five cases of PMC were examined immunohistochemically, including 11 cases less than 5 mm (PMC < 5) and 24 cases more than 5 mm (PMC > 5), and 18 PTC cases (size 11-15 mm). Cyclin D1 expression was significantly lower in PMC < 5 than in PMC > 5, while there was no significant difference between PMC > 5 and PTC. Statistical analysis revealed significant correlations between cyclin D1 labelling index (LI) and Ki67 LI (P = 0.0272)/cytoplasmic beta-catenin expression (P < 0.001) in PMC and PTC. Four of five PMC > 5 cases with lymph node (LN) metastases displayed a high cyclin D1 LI and strong cytoplasmic beta-catenin expression.. Cyclin D1 overexpression and correlation with aberrant beta-catenin expression were demonstrated in PMC. Cyclin D1 expression was significantly associated with tumour size and LN metastases in PMC. Cyclin D1 may be up-regulated at an early stage of thyroid carcinogenesis and promote tumour growth and metastatic potency in PMC through activation of the Wnt/beta-catenin pathway.

Topics: Adult; beta Catenin; Carcinoma, Papillary; Cyclin D1; Cytoskeletal Proteins; Humans; Immunohistochemistry; Ki-67 Antigen; Lymphatic Metastasis; Middle Aged; Thyroid Neoplasms; Trans-Activators

The aim of the study was to demonstrate and evaluate the expression of cyclin D1, a protein connected with a cell cycle, by means of the immunohistochemical method in malignant thyroid neoplasms. The purpose of the analysis of the results was to explain the relation between cyclin D1 in thyroid cells and neoplasm transformation.. The study was conducted on thyroid neoplasms from 35 patients who were diagnosed with the thyroid carcinoma (30 women and 5 men). Detection DAKO LSAB + system was applied with use of monoclonal antibodies against cyclin D1. The results of immunohistochemical reaction was described as an index (percentage of cells showing a characteristic brown color in 1000 counted cells). As a positive result of reaction an intensive brown color of carcinomas cellular nuclei was acknowledged.. The mean value of cyclin D1 expression index in papillary carcinoma was 14.44% +/- 9.37, in medullary carcinoma 27.35% +/- 5.40, in nonpapillary carcinomas originating from A cells 18.0% +/- 10.20. The results were statistically analyzed. In medullary carcinoma the highest values of positive cells cyclin D1 index were revealed.. The results obtained encourage continued studies on cyclin D1 expression in thyroid neoplasms and a more accurate analysis with a larger number of cases. Perhaps the index of this protein will become a recognized prognostic marker in thyroid neoplasms or an objective risk factor of the thyroid epithelial cells neoplastic transformation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma; Carcinoma, Medullary; Carcinoma, Papillary; Cell Transformation, Neoplastic; Cyclin D1; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Thyroid Neoplasms

We investigated the status of the components and target genes of the Wnt signaling pathway in Japanese anaplastic thyroid cancers (ATCs) in the present study. Nuclear and cytoplasmic positive staining of beta-catenin, which might indicate the existence of alterations in the Wnt signaling pathway, were found in 40.9% and 63.6% of the 22 ATC samples, respectively. The beta-catenin, adenomatous polyposis coli (APC) and Axin 1 gene mutations were observed in 4.5%, 9.0%, and 81.8% of the 22 ATC samples, respectively. Overexpression of cyclin D1 and c-myc, which are the target genes of the Wnt signaling pathway, was observed in 27.3% and 59.1% of the ATC samples, respectively. There was no significant correlation between nuclear or cytoplasmic positive staining of beta-catenin and nuclear positive staining of cyclin D1 or c-myc. Taken together, the results of beta-catenin immunohistochemistry suggest that alterations in the Wnt signaling pathway are associated with carcinogenesis of ATC, but the frequency of beta-catenin gene mutation in our series is lower than that previously reported. Furthermore, cyclin D1 and c-myc frequently accumulated in ATC, independently of dysfunction in the Wnt signaling pathway.

Topics: Adenoma; Aged; Aged, 80 and over; Axin Protein; beta Catenin; Carcinoma; Carcinoma, Papillary; Cyclin D1; Cytoskeletal Proteins; DNA, Neoplasm; Female; Genes, myc; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Japan; Male; Middle Aged; Mutation; Repressor Proteins; Signal Transduction; Thyroid Neoplasms; Trans-Activators; Wnt Proteins

The Semipalatinsk nuclear test site (SNTS), the Republic of Kazakhstan, has been contaminated by radioactive fallout. The alteration of oncogenic molecules in thyroid cancer around the SNTS was considered worthy of analysis because it presented the potential to elucidate the relationship between radiation exposure and thyroid cancer. This study aimed to analyze both beta-catenin and cyclin D1 expressions in thyroid carcinomas around the SNTS. We examined nine cases of chronic thyroiditis, eight cases of follicular adenomas, and 23 cases of papillary carcinomas. Immunohistochemically, all carcinomas displayed a strong cytosolic beta-catenin expression, while both chronic thyroiditis and follicular adenomas showed a significantly lower cytoplasmic beta-catenin (22.2% and 37.5%, respectively). No cyclin D1 immunoreactivity was evident in chronic thyroiditis. In contrast, 62.5% of follicular adenomas and 87.0% of papillary carcinoma showed cyclin D1 overexpression. Additionally, a strong correlation between cytoplasmic beta-catenin and cyclin D1 expression was suggested in thyroid tumors. This study revealed a higher prevalence of both aberrant beta-catenin expression and cyclin D1 overexpression in papillary thyroid cancers around the SNTS than sporadic cases. The analysis of the alteration of the Wnt signaling-related molecules in thyroid cancer around the SNTS may be important to gain an insight into radiation-induced thyroid tumorigenesis.

Topics: Adolescent; Adult; Aged; beta Catenin; Carcinoma, Papillary; Cell Membrane; Cyclin D1; Cytoplasm; Cytoskeletal Proteins; Female; Humans; Immunohistochemistry; Kazakhstan; Male; Middle Aged; Neoplasms, Radiation-Induced; Nuclear Warfare; Prevalence; Radioactive Fallout; Thyroid Gland; Thyroid Neoplasms; Trans-Activators

Cyclin D1 and E2F-1 proteins are essential for the regulation of the G1/S transition through the cell cycle. Cyclin D1, a product of the bcl-1 gene, phosphorylates the retinoblastoma protein, releasing E2F-1, which in turn activates genes involved in DNA synthesis. Expression patterns of E2F-1 protein in thyroid proliferations have not been reported. This study used monoclonal antibodies for cyclin D1 and E2F-1 proteins to immunostain sections of normal thyroid, hyperplastic (cellular) nodules, follicular adenomas, follicular carcinomas, and papillary carcinomas. The proliferation rate was examined using an antibody specific for the Ki-67 antigen. Fluorescence in situ hybridization (FISH) methods and chromosome 11-specific probes were also employed to determine chromosome copy number and to assess for evidence of amplification at the 11q13 locus in papillary and follicular carcinomas with cyclin D1 overexpression. Concurrent overexpression of Ki-67, cyclin D1, and E2F-1 was found in the majority of benign and malignant thyroid lesions, compared with normal thyroid tissue. Cyclin D1 up-regulation was not due to extra copies of chromosome 11, or bcl-1 gene amplification. Malignant tumours showed the highest expression for all three markers, particularly papillary carcinomas. E2F-1 was detected at the same or slightly lower levels than cyclin D1. It was only found when cyclin D1 was overexpressed. Because cyclin D1 normally activates E2F-1, up-regulation of cyclin D1 may lead to E2F-1 overexpression in benign and malignant thyroid lesions.

Topics: Adenocarcinoma, Follicular; Adenoma; Carcinoma, Papillary; Cell Cycle Proteins; Cell Division; Cyclin D1; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; Humans; Hyperplasia; In Situ Hybridization, Fluorescence; Ki-67 Antigen; Neoplasm Proteins; Thyroid Gland; Thyroid Neoplasms; Transcription Factors

Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27(Kip1), p21(Waf1) and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (> or =25% positive nuclei) was significantly associated with p53 gene mutation (p = 0.012), low p21(Waf1) (p = 0.015) and high p27(Kip1) (p = 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (> or =10% positive nuclei) was significantly associated with high tumor grade (p = 0.001) and with DNA aneuploidy (p = 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p = 0.003). Both cyclin D1 (p = 0.027; RR = 1.898) and Ki67 (p = 0.047; RR = 1.932) protein expressions were independent predictors of reduced disease-free survival on a multivariate analysis that also included p27(Kip1) expression and tumor stage. The simultaneous presence of low cyclin D1, low p27(Kip1) and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Papillary; Cell Cycle Proteins; Cell Division; Cohort Studies; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Ploidies; Predictive Value of Tests; Prognosis; Receptor, ErbB-2; Risk Assessment; Tumor Suppressor Proteins; Urinary Bladder Neoplasms

Overexpression of cyclin D1 occurs in several malignancies, often due to gene amplification, and this has been associated with aggressive tumor behavior, a higher incidence of lymph node metastases, and a poorer prognosis. The role of cyclin D1 in the pathogenesis of thyroid malignancy is unknown; however, cyclin D1 expression has been reported to occur in a proportion of well differentiated thyroid carcinomas. Micropapillary carcinomas of the thyroid are common incidental findings that almost always behave in an indolent manner and remain quiescent. However, rare microcarcinomas behave aggressively and metastasize early, giving rise to clinically significant disease. We hypothesized that cyclin D1 might play a role in the aggressive behavior of metastasizing papillary microcarcinomas. We reviewed the histopathology reports of 2,000 patients who underwent thyroid surgery at our institution between 1995-1999 and identified 22 patients who presented with gross regional metastases from a primary papillary microcarcinoma. These patients formed the index cohort for this analysis. As controls, we selected 34 patients with nonmetastasizing microcarcinomas. We studied these tumors for immunoreactivity to cyclin D1 on immunohistochemistry and analyzed 13 tumors that diffusely expressed cyclin D1 for gene amplification by differential PCR. Twenty of the 22 (90.9%) metastasizing papillary microcarcinomas expressed cyclin D1, compared with 3 of the 34 (8.8%) nonmetastasizing papillary microcarcinomas (P < 0.001). However, of the 13 tumors that showed diffuse immunoreactivity for cyclin D1 on immunohistochemistry, none showed amplification of the cyclin D1 gene on differential PCR. We conclude that cyclin D1 is significantly overexpressed in metastasizing papillary microcarcinomas of the thyroid. This is likely due to mechanisms other than gene amplification. Cyclin D1 immunohistochemistry may be a valuable tool in predicting metastatic potential in papillary microcarcinomas.

Topics: Carcinoma, Papillary; Cohort Studies; Cyclin D1; Gene Amplification; Humans; Immunohistochemistry; Prognosis; Thyroid Neoplasms

Lymph node metastasis in papillary thyroid carcinoma increases the morbidity of treatment and the risk of local regional relapse and may also affect cure rates and survival. Factors that predict lymph node metastasis are, however, unclear. We analyzed 125 patients with papillary thyroid carcinoma for factors that predict lymph node metastasis. On univariate analysis, age, extrathyroidal extension, tumor focality, overexpression of cyclin D1, and underexpression of p27 predicted lymph node metastasis, whereas patient gender and tumor size did not. On multivariate analysis, extrathyroidal extension, overexpression of cyclin D1, and underexpression of p27 proved to be strong independent predictors of lymph node metastasis. We suggest that immunohistochemistry for cyclin D1 and p27 will prove valuable in identifying papillary thyroid carcinomas with metastatic potential.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Papillary; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Prognosis; Thyroid Neoplasms; Tumor Suppressor Proteins

Aberrations in the G1/S checkpoint are common in malignancies and are probably important for tumor development. Few G1/S studies have been performed on renal cell carcinoma (RCC) and therefore in this study the cyclin D3 protein content in 80 RCCs and that in 12 corresponding normal kidney cortex tissues are characterized using Western blotting. High cyclin D3 protein content was observed in 16% of the tumors and was significantly associated with aneuploidy, high TNM stage, high nuclear grade, high proliferation and young age. There was no association between tumor cyclin D3 and patient survival. The cyclin D3 overexpression was confirmed by immunohistochemical staining of 72 tumors, showing both nuclear and cytoplasmic localization of cyclin D3 in a fraction of the tumors. The cyclin D1 content has earlier been characterized in this tumor material and there was no relation between cyclin D1 and cyclin D3 protein expression. In summary, a fraction of the tumors overexpressed cyclin D3, supporting that various aberrations in the G1/S transition are implicated in RCCs.

Topics: Adrenal Cortex; Aged; Carcinoma, Papillary; Carcinoma, Renal Cell; Cell Nucleus; Cyclin D1; Cyclin D3; Cyclins; Cytoplasm; Female; Humans; Immunoenzyme Techniques; Kidney Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Ploidies; Survival Rate

Alterations of the Wnt/beta-catenin signaling pathway are known to occur in mutations of the component genes such as APC, Axin, and beta-catenin, and play a pathogenetic role in tumorigenesis. Activated Wnt signaling stabilizes beta-catenin, which associates with T cell factor, resulting in transactivation of the downstream target genes including c-myc and cyclin D1. To investigate the involvement of Wnt/beta-catenin signaling pathway in thyroid tumorigenesis, we analyzed its activation and localization in 5 human thyroid cancer cell lines and 132 thyroid tumor tissue samples. Dislocalization of beta-catenin was observed in all cell lines. Constitutive activation of T cell factor in two of four thyroid cancer cell lines was observed using reporter gene assay. Furthermore, high expression levels of c-Myc and cyclin D1 were observed in cell lines that showed cytoplasmic or nuclear accumulation of beta-catenin. In 132 paraffin-embedded thyroid carcinoma tissue samples, cytoplasmic beta-catenin was immunohistochemically observed in 52 out of 78 (67%) papillary thyroid cancers, but only in 3 of 34 (9%) follicular adenomas and 5 of 20 (25%) follicular cancers. Cytoplasmic localization of beta-catenin significantly correlated with overexpression of cyclin D1 in papillary carcinomas. Our results suggest that aberrant activation of Wnt/beta-catenin signaling is strongly involved in thyroid tumorigenesis.

Topics: Adenocarcinoma, Follicular; Adenoma; Adenomatous Polyposis Coli Protein; Axin Protein; beta Catenin; Carcinoma, Papillary; Cells, Cultured; Cyclin D1; Cytoskeletal Proteins; DNA Mutational Analysis; Gene Expression; Humans; Immunohistochemistry; Proteins; Repressor Proteins; TCF Transcription Factors; Thyroid Neoplasms; Tissue Distribution; Trans-Activators; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transcriptional Activation

Cell growth and proliferation depend on protein synthesis that is regulated, in part, by two eukaryotic translation initiation factors, eIF-4E and eIF-2alpha. These factors are transiently increased as normal cells respond to growth factors and are constitutively elevated in transformed cells. In cultured cells, eIF-4E facilitates cell cycle progression by increasing the expression of cell cycle promoting proteins including cyclin D1. Our previous study revealed elevated cyclin D1 expression in histologically more aggressive thyroid carcinomas as compared to conventional papillary carcinoma. We hypothesized that the increased cyclin D1 expression might correlate with increased eIF-4E expression. We, therefore studied the expression of eIF-4E by immunohistochemistry in 25 cases of conventional papillary carcinoma (CPC) and 28 cases of aggressive thyroid carcinomas (ATC), the latter included 11 tall cell/columnar cell variant of papillary carcinoma, 5 insular carcinomas, and 12 anaplastic carcinomas. We also analyzed the expression of eIF-2a in the same samples as this factor is usually regulated similarly to eIF-4E in cell culture models. Of the 25 CPC, 13 were eIF-4E positive (11 weakly and 2 strongly), and 19 were eIF-2a positive (14 weakly and 5 strongly). Conversely, of the 28 ATC, 25 were eIF-4E positive (4 weakly and 21 strongly), and 23 were eIF-2alpha positive (4 weakly and 19 strongly). There was a significantly increased expression of both eIF-4E (p < 0.001) and eIF-2alpha (p < 0.001) in ATC compared to CPC, suggesting that these translation initiation factors may play a role in the progression of thyroid cancer.

Topics: Antibody Specificity; Blotting, Western; Carcinoma; Carcinoma, Papillary; Cell Division; Cyclin D1; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Humans; Immunohistochemistry; Keratins; Peptide Initiation Factors; Thyroid Neoplasms

Solid pseudopapillary tumor of the pancreas was studied in a 20-year-old woman and a 54-year-old woman. In the younger patient, the tumor had metastasized to the liver 8 years after distal pancreatectomy. In both neoplasms, the distinct histologic pattern of solid, pseudopapillary, and degenerative cystic areas was present. Analysis by means of immunohistochemistry revealed a diffuse expression for vimentin, neuron-specific enolase, and a focal positivity for al-antitrypsin, whereas epithelial markers were negative in the tumor of the older patient and only focally expressed in the tumor of the younger patient. Immunohistochemical analysis of cell cycle-associated proteins provided an overexpression of cyclin D1 and cyclin D3 in both tumors, although to varying degrees. In addition, the cyclin-dependent kinase inhibitors p21, and to a lesser extent p27, were up-regulated just as mdm2. There was no accumulation of p53 protein, and Ki67-positive cells were extremely scarce. Analysis of the liver metastases showed an immunoreactive profile similar to that of the primary tumor. The results show a deregulation of the cell cycle with overexpression of cell cycle-activating proteins D1 and D3 and a probably counterbalancing upregulation of the cyclin-dependent kinase inhibitors p21 and p27. The findings may explain the low pool of Ki67-reactive tumor cells and the generally good clinical outcome of these tumors. Whether a more profound dysbalance of the cell cycle regulation is responsible for the development of metastatic disease remains to be clarified.

Topics: Biomarkers, Tumor; Carcinoma, Papillary; Child; Cyclin D1; Cyclin D3; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Enzyme Inhibitors; Female; Humans; Microfilament Proteins; Middle Aged; Muscle Proteins; Pancreatic Neoplasms; Up-Regulation

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.

Topics: Adenoma; Adult; Carcinoma; Carcinoma, Papillary; Carcinoma, Papillary, Follicular; Cyclin D1; Gene Dosage; Genes, erbB-2; Genes, myc; Goiter, Nodular; Humans; Middle Aged; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Gland; Thyroid Neoplasms

The aim of the study was an evaluation of expression of D1 cyclin and Ki-67 proteins in tissue of human papillary thyroid carcinoma (PTC) in a group of papillary microcarcinomas and in a group of PTC with a degree of staging higher than pT1a in TNM classification. We performed immunohistochemical staining and found no statistical differences between groups. These results suggest that changes of expression of D1 cyclin are an early event in tumorigenesis.

Topics: Adult; Carcinoma, Papillary; Cyclin D1; Female; G1 Phase; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; S Phase; Thyroid Neoplasms

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.

Topics: Adenocarcinoma, Follicular; Carcinoma, Papillary; Cell Count; Cyclin D1; Disease Progression; Fluorescent Antibody Technique, Indirect; Humans; Thyroid Neoplasms

Cyclin D1 is a G1 cyclin participating in the control of cell cycle progression through interaction with the retinoblastoma gene product (pRB). The overexpression of positive regulators (such as cyclin D1) has been reported in a variety of neoplasms, but their role in thyroid tumorigenesis is yet to be established. In our series of 54 thyroid carcinomas, cyclin D1 overexpression (detected by both immunohistochemistry and by Northern blotting) was correlated with prognostic variables, proliferative activity and pRB. Cyclin D1 overexpression was observed in 35% of thyroid carcinomas with a significantly higher expression of this cyclin in neoplastic tissues than in matched normal parenchyma. In well-differentiated carcinomas, the cyclin D1 mRNA overexpression was inversely correlated with nodal status (p = 0.03), while the protein product was higher in tumors from patients less than 40 than patients over 40 years of age. Inversely, there was no significant correlation with gender and tumor status, pRB and with proliferative activity.

Topics: Adenocarcinoma, Follicular; Blotting, Northern; Carcinoma, Medullary; Carcinoma, Papillary; Cell Division; Cyclin D1; Gene Expression; Genes, Retinoblastoma; Humans; Immunohistochemistry; Ki-67 Antigen; Prognosis; RNA, Messenger; Thyroid Neoplasms

To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid.. Resistance to transforming growth factor beta-mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor beta receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years.. Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis.. Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases.. The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27kip. This would maintain cells in a proliferative state and would promote tumor progression.

Topics: Adult; Biomarkers, Tumor; Carcinoma, Papillary; Cell Cycle; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Female; Follow-Up Studies; Humans; Male; Microtubule-Associated Proteins; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Transforming Growth Factor beta; Thyroid Gland; Thyroid Neoplasms; Tumor Suppressor Proteins

Papillary carcinoma of the thyroid is the most common thyroid cancer. At the time of clinical presentation, most papillary carcinomas are still confined to the thyroid gland, and appropriate surgical treatment achieves a 95% 5-year survival rate. Certain carcinomas, however, behave in a much more aggressive fashion. Because specific therapies do not exist, for those tumors that have escaped local control, patients with disseminated disease have little or no chance of permanent cure or long-term survival. Cyclin D1, a protein that plays a critical role in the control of the cell cycle, has been shown to be overexpressed in a variety of human neoplasias and may serve as a prognostic parameter of disease progression. To explore the role played by cyclin D1 in the pathogenesis of thyroid papillary carcinoma, we have quantitated, by computerized image analysis, the immunohistochemical expression of cyclin D1 in formalin-fixed, paraffin-embedded tissue from 35 conventional papillary carcinomas of the thyroid and correlated the results with established clinicopathologic parameters and available survival data.

Topics: Adult; Aged; Carcinoma, Papillary; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 11; Cyclin D1; Female; Follow-Up Studies; Genes, bcl-1; Humans; Male; Middle Aged; Neoplasm Staging; Point Mutation; Prognosis; Thyroid Neoplasms

Distinguishing intraductal papilloma from papillary carcinoma of the breast can be difficult using histologic criteria. Since cyclin D1, a G1 cell-cycle regulatory protein, is detectable immunohistochemically in a subset of breast carcinomas but not in benign breast tissues, we hypothesized that cyclin D1 immunoreactivity may be a marker for identifying papillary carcinoma.. Using an immunohistochemical method, we assessed for cyclin D1 expression in 8 breast papillomas and 6 papillary carcinomas, all of which were formalin fixed, routinely processed, and paraffin embedded. Cyclin D1 positivity also was compared with the overall proliferation rate, which was assessed by using the proliferation marker Ki-67. In each case, a 200-cell count was performed to obtain the percentage of cells positive for these 2 markers.. The percentage of cyclin D1-positive cells was significantly higher in papillary carcinomas (89%+/-18%; range, 53%-98%) than in papillomas (8%+/-7%; range, 0%-19%). This difference was highly statistically significant (P < .0001). Although the difference in Ki-67 positivity between these 2 groups was also statistically significant (P = .01), separation of papillary carcinomas and papillomas by Ki-67 immunoreactivity was less clear because of overlapping values between groups: 13% +/-6%; range, 9% to 23% for papillary carcinomas versus 8%+/-2%; range, 6% to 12% for papillomas.. These results support the notion that cyclin D1 is a useful marker for distinguishing breast papillomas from papillary carcinomas. The marker Ki-67 is also helpful, but is less useful than cyclin D1, owing to the overlap in Ki-67 results in papillomas and papillary carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinoma, Papillary; Cyclin D1; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Middle Aged; Papilloma

Cyclin D1 plays a key role in the regulation of the G1/S transition through the cell cycle. Deregulation of cyclin D1, most often leading to overexpression of the gene, has been reported in many tumor types. It has been suggested that cyclin D1 overexpression could be an alternative mechanism for pRb inactivation. We have previously found Rb gene mutations in 55% of malignant thyroid tumors. In the present study, we examined the cyclin D1 gene expression and amplification in 24 tumor samples (two of them are benign goiters) randomly selected from the same series of thyroid tumors, to see whether cyclin D1 overexpression is present in those specimens without Rb gene mutations. We found a four- to fivefold increase in cyclin D1 expression in 7 of 22 thyroid carcinomas as compared with that in benign nodular goiters. Six of them were found in carcinomas without Rb gene mutations. Among the remaining 15 thyroid carcinoma samples, 11 were found previously to have Rb gene mutations. The association between increased cyclin D1 expression and absence of Rb mutation is statistically significant (p < 0.05). We found no evidence of the cyclin D1 gene amplification or rearrangement to account for such an increase in cyclin D1 expression. We conclude that cyclin D1 overexpression may be relevant to thyroid carcinogenesis. Two mechanisms may be involved in the inactivation of pRb: one is through Rb gene mutations, and the other is by cyclin D1 overexpression.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Blotting, Northern; Blotting, Southern; Carcinoma; Carcinoma, Papillary; Cyclin D1; Female; Gene Expression; Genes, Retinoblastoma; Goiter, Nodular; Humans; Male; Middle Aged; Mutation; Thyroid Neoplasms

The cell cycle is controlled in part by cyclin-dependent kinases (CDKs), which are activated by forming complexes with cyclins. CDKs phosphorylate certain substrates to facilitate the proliferating cells through the cell cycle. CDK inhibitors (CDKIs) such as p27 inhibit cyclin-CDK complexes and function as a negative cell cycle regulator. The overexpression of the positive regulators (cyclins) or the underexpression of the negative regulators including p27 has been seen in a variety of neoplasms, but their role and interaction in thyroid carcinogenesis is yet to be established. We studied the expression of cyclins D1 and E, and the CDKI, p27 by immunohistochemistry in 116 cases, including 59 cases of follicular variant of papillary carcinoma (FVPC) and 57 cases of follicular adenoma (FA). The positive staining was divided into four grades: 1+ if less than 10%, 2+ if 11% to 25%, 3+ if 26% to 50%, and 4+ if greater than 50% of the nuclei of tumor cells stained positively. Cyclin D1 expression was seen in 37 (63%) FVPC and 34 (60%) FA. Cyclin E-positive cells were seen in 51 (86%) FVPC and 47 (82%) FA. No significant differences in the grade of cyclins D1 (P = .261) and E (P = .284) staining was seen between FVPC and FA. Of the 59 FVPC, 53 (89%) showed p27-positive cells; of these, 33 were 1+, nine were 2+, seven were 3+ and only four were 4+ positive. Conversely, all 57 FA were p27 positive, 53 were 4+, and four were 3+ positive. This difference in the grade of p27 staining between FVPC and FA was statistically significant (P < .001). This study shows a significant underexpression of p27 in FVPC compared with FA, suggesting that a decrease in p27 expression plays a more important role than overexpression of cyclins D1 and E alone in thyroid carcinogenesis and that p27 immunostaining may be helpful in the diagnosis of FVPC.

Topics: Adenocarcinoma, Follicular; Adenoma; Carcinoma, Papillary; Cell Cycle; Cell Cycle Proteins; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p27; Humans; Immunohistochemistry; Microtubule-Associated Proteins; Thyroid Neoplasms; Tumor Suppressor Proteins

Cyclin D1 plays an important role in cell cycle progression from G1 to S phase. Cyclin D1 overexpression has been identified in many human neoplasms, including a variety of carcinomas. A systematic study of cyclin D1 expression in renal carcinomas and oncocytomas has not been reported. Ninety-six renal epithelial neoplasms, 78 renal carcinomas (45 clear-cell, 18 papillary, and 15 chromophobe), and 18 oncocytomas were analyzed immunohistochemically using routinely fixed tissue sections and a cocktail of two monoclonal anti-cyclin D1 antibodies. One thousand cells were manually counted, and the percentage of cyclin D1 positive cells was calculated. Fluorescence in situ hybridization studies using chromosome 11 centromeric and 11q13 specific probes were performed on a subset of clear-cell carcinomas and oncocytomas. Cyclin D1 immunoreactivity was observed in 23 (51%) of 45 clear-cell, 5 (28%) of 18 papillary, and 2 (13%) of 15 chromophobe carcinomas. Nine (50%) of 18 oncocytomas were positive for cyclin D1. Cyclin D1 expression in clear-cell carcinomas did not correlate with survival. Fluorescence in situ hybridization studies on eight clear-cell carcinomas and seven oncocytomas revealed normal chromosome 11 number and no evidence of amplification of the 11q13 locus. Thus, cyclin D1 can be immunohistochemically demonstrated in approximately one-half of renal oncocytomas and clear-cell carcinomas and is less frequent in papillary and chromophobe carcinomas. The mechanism of cyclin D1 expression is unknown, but it does not seem to be related to extra copies of chromosome 11 or to gene amplification.

Topics: Adenocarcinoma; Adenocarcinoma, Clear Cell; Adenoma, Oxyphilic; Carcinoma, Papillary; Carcinoma, Renal Cell; Cell Nucleus; Cyclin D1; Disease-Free Survival; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kidney Neoplasms; Survival Analysis