cyclin-d1 and Salivary-Gland-Neoplasms

The objective of this retrospective study was to explore possible changes in histopathological features and expression of cyclin D1 and MIB-1 in salivary gland pleomorphic adenoma (PA) that recur or undergo malignant transformation. Knowledge of these characteristics might help to guide the management of these rare tumors. The histopathology and immunohistochemical staining characteristics of such tumors were analyzed in a cohort of 65 patients constituting three different groups of tumors: PA, recurrent pleomorphic adenoma (RPA) and carcinoma ex PA (CxPA). The RPAs were divided into two subgroups: primary PA that were known to recur later (PA-prim) and recurrent tumors appearing after a primary tumor (PA-rec). RPAs and CxPAs were compared with PAs without recurrence, which served as a control group. In our study, CxPA and PA-rec, but not PA-prim, showed increased MIB-1 expression compared with the control group. Neither cyclin D1 expression nor any histopathological features showed any association in statistical analyses. CxPA showed increased mitotic activity, squamous metaplasia, and nuclear atypia. Tumor multifocality was more frequent in PA-rec and CxPA. The different MIB-1 expression in CxPA and PA-rec in comparison to PA-prim suggests that the changes in expression could develop after the primary tumor.

Topics: Adenoma, Pleomorphic; Cell Transformation, Neoplastic; Cyclin D1; Humans; Retrospective Studies; Salivary Gland Neoplasms; Salivary Glands; Ubiquitin-Protein Ligases

Conventional acinic cell carcinoma (CACC) represents a prototypical low-grade salivary malignancy. Rarely, acinic cell carcinoma (ACC) can demonstrate aggressive features (zones of necrosis, apoptosis, varying nuclear atypia) warranting classification as "ACC with high-grade transformation" (HGT-ACC) or "dedifferentiated" ACC. This study reports ten new cases of HGT-ACC. There is potential for subtlety in recognizing high-grade transformation and distinguishing discrete nodules of necrosis from cytology aspiration changes. We compared immunohistochemical (IHC) profiles, specifically β-catenin (bCAT) and cyclin D1 expression, which have been touted as potentially helpful in this context. We quantified morphology (primary axis nucleus, nuclear area and perimeter) in HGT-ACC and CACC. Clinical outcome is known for eight HGT-ACC patients; three patients developed locoregional or distant metastases, five remained disease-free. Nine of ten HGT-ACC expressed strong, diffuse, membranous bCAT. CACC demonstrated lower intensity of membranous bCAT expression. Strong, diffuse nuclear cyclin D1 was seen in five of ten HGT-ACC whereas no CACC demonstrated cyclin D1 with distribution greater than 50 %. The quantified nuclear morphologic features of CACC and HGT-ACC demonstrated overlapping means values. Maximum values for nuclear primary axis, area, and perimeter were greater for HGT-ACC versus CACC, corresponding to a subpopulation of larger tumor cells in HGT-ACC. The poor outcome associated with HGT-ACC justifies its recognition, which should alter surgical approach with respect to elective neck dissection or possible facial nerve sacrifice. With respect to ancillary IHC studies, strong, diffuse membranous bCAT expression, with or without strong nuclear cyclin D1 ≥ 50 % distribution or Ki67 index ≥ 25 % supports this diagnosis.

Topics: Adult; Aged; beta Catenin; Carcinoma, Acinar Cell; Cell Nucleus; Cell Transformation, Neoplastic; Cyclin D1; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Prognosis; Salivary Gland Neoplasms

Salivary gland tumors are complex and have a great histomorphological diversity; more than 30 histological subtypes are currently described and the study of proteins that help understand and differentiate these tumors is essential. We aimed to analyze the immunoexpression of cyclooxygenase-2 (COX-2) and cyclin D1 proteins in pleomorphic adenomas (PA), mucoepidermoid carcinomas (MEC) and adenoid cystic carcinomas (AdCC) of salivary glands.. A total of 38 PA, 12 AdCC and 12 MEC underwent immunohistochemical study by the polymeric biotin-free technique. Immunopositive cells were analyzed semi-quantitatively. For statistical analysis, a significance level was set at p ≤ 0.05.. Overall, these tumors were more prevalent in women (n = 37). The mean age of these patients was 58-year-old and the parotid gland was the most affected anatomic site (n = 33). All cases of AdCC and MEC showed immunopositivity to cyclin D1; however, 39.5% of the PAs were negative (p < 0.001). Regarding COX-2 immunoexpression, we observed that all cases of CME were positive, whereas 60.5% of the PA and 75% of the CAC analyzed were completely negative (p = 0.042).. The overexpression of COX-2, observed only in MEC, emphasizes that salivary gland tumors have different profiles. Cyclin D1 is more immunoexpressed in malignant tumors. Together, these immunohistochemical findings may be useful in differentiating the studied tumors.

Topics: Adenoma, Pleomorphic; Adult; Biomarkers, Tumor; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Cyclin D1; Cyclooxygenase 2; Female; Humans; Male; Middle Aged; Salivary Gland Neoplasms

Adenoid cystic carcinoma (ACC) is an intriguing lesion because it shows a slow growth in the beginning, but a late poor prognosis due to perineural invasion, metastasis and recurrence. This study aimed to investigate whether Akt signaling would be deregulated in adenoid cystic carcinoma and its consequence in the expression of associated proteins.. The expression of the Akt, p-Akt, NFκB, β-catenin, cyclin D1 and COX-2 was assessed by immunohistochemistry in 10 cases of ACC, 17 cases of pleomorphic adenoma (PA), and 7 cases of normal salivary gland (NSG).. p-Akt was overexpressed in ACC when compared to NSG. NFκB, β-catenin, and COX-2 were overexpressed in ACC and PA when compared to NSG. Most proteins were slightly higher expressed in ACC than in PA, but they never reached significance. p-Akt expression positively correlated with NFκB, β-catenin, cyclin D1 and COX-2 in ACC and PA, while this correlation trended to be negative in for these proteins (except for NFκB) in NSG using Person's correlation analysis, but without reaching significance.. Our results indicate an abnormal activation of Akt signaling pathway, which can be an important regulator of tumor biology in ACC. Activated Akt correlated with the expression of NFκB, β-catenin and COX-2, which can potentially influence cell survival in ACC.

Topics: Adenoma, Pleomorphic; beta Catenin; Carcinoma, Adenoid Cystic; Cyclin D1; Cyclooxygenase 2; Humans; Immunohistochemistry; NF-kappa B p50 Subunit; Proto-Oncogene Proteins c-akt; Salivary Gland Neoplasms; Salivary Glands; Signal Transduction

Minor salivary gland carcinoma is a rare and heterogeneous type of cancer. Molecular prognostic and predictive markers are sparse. The aim of this study was to identify new prognostic and predictive markers in minor salivary gland carcinoma. 50 tissue samples of carcinomas of the minor salivary glands (adenoid cystic carcinoma n = 23, mucoepidermoid carcinoma n = 12, adenocarcinoma n = 10, carcinoma ex pleomorphic adenoma n = 2, salivary duct carcinoma n = 1, clear cell carcinoma n = 1, basal cell carcinoma n = 1) were immunohistochemically stained for β-catenin, cyclin D1 and PIN1. Expression patterns were analyzed and correlated to clinical outcome of 37 patients with complete clinical data. High expression of membranous β-catenin was linked to significantly better overall survival in patients with adenoid cystic carcinoma (log rank test, χ (2) = 13.3, p = .00397, Bonferroni corrected p = .024). PIN1 and cyclin D1 did not show any significant correlation to patients' clinical outcome. Expression of β-catenin in adenoid cystic carcinoma of the minor salivary glands significantly correlates with better overall survival. Hence, evaluation of β-catenin might serve as a clinical prognostic marker.

Topics: Austria; beta Catenin; Biomarkers, Tumor; Carcinoma, Adenoid Cystic; Cyclin D1; Female; Humans; Male; Middle Aged; NIMA-Interacting Peptidylprolyl Isomerase; Outcome Assessment, Health Care; Predictive Value of Tests; Prognosis; Retrospective Studies; Salivary Gland Neoplasms; Salivary Glands, Minor; Statistics as Topic; Survival Analysis

Pim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed.. SACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells' invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry.. Pim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues.. This study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer.

Topics: Biomarkers, Tumor; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cell Proliferation; Core Binding Factor Alpha 3 Subunit; Cyclin D1; Cyclin-Dependent Kinase 4; Humans; Oncogenes; Proto-Oncogene Proteins c-pim-1; RNA Interference; RNA, Small Interfering; Salivary Gland Neoplasms; Survival Analysis

Salivary gland tumors (SGT) are a heterogeneous group of lesions. There is conflicting data concerning the molecular events involving the tumour suppressor retinoblastoma protein (pRb) pathway in these tumors. Few studies examined the alterations in components of the Rb pathway by immunohistochemical (IHC) methods in benign and malignant SGTs. Furthermore, recent evidence implicates human papillomavirus (HPV) in mucoepidermoid carcinoma (MEC) carcinogenesis. The purpose of our study is to examine p16(INK4A) and cyclin D1 expression in a variety of benign and malignant salivary gland tumors, and to investigate p16(INK4A) expression as a surrogate marker for HPV infection in MEC. Our series includes 30 malignant tumors [14 MEC, 6 acinic cell carcinomas (ACC), 5 polymorphous low grade adenocarcinomas (PLGA), 5 (AdCC)] and 14 benign tumors (4 benign cysts, 5 Warthin tumors and 5 pleomorphic adenomas (PA). All cases were tested by IHC for p16(INK4A) and cyclin D1. Testing for HPV wide spectrum (HPV-WS) was performed by in situ hybridization in all MEC cases. Staining intensity was recorded semi quantitatively (on a scale from 0 to 4+). Fisher's exact test and Pearson X2 test with a p < 0.05 were used. Cyclin D1 and p16(INK4A) are expressed similarly in malignant and benign tumors (p = 0.146 and p = 0.543, respectively). None of the MEC cases showed nuclear reactivity for HPV-WS. Statistical analysis showed positive correlation between cyclin D1 and p16(INK4A) expression. Our findings suggest that p16(INK4A) overexpression is likely secondary to cyclin D1 gene upregulation or amplification. Further molecular studies are warranted.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Humans; Immunohistochemistry; Male; Middle Aged; Salivary Gland Neoplasms; Young Adult

Adenoid cystic carcinoma (ACC), commonly from salivary glands, is known for its insidious local growth and usually protracted clinical course. ACC developing from non-salivary glands (i.e., non-salivary ACC) is heterogeneous, and its clinicopathological features remain poorly defined. Patients treated for ACC in a single institution between 1995 and 2007 were included in this study. Immunohistochemical evaluation of Ki-67, E-cadherin, p16, and cyclinD1 was performed. The prognostic significance of clinical and immunophenotypic markers was evaluated. 83 cases of salivary ACC and 24 cases of non-salivary ACC were included. The expression levels of Ki-67 (54.8%), E-cadherin (90.4%), p16 (32.9%), and cyclinD1 (19.2%) between ACCs present at various sites were not different. Sinonasal, lacrimal, and tracheobronchial ACCs had significantly worse outcomes than those of ACC of the major salivary glands. Postoperative radiotherapy reduced the recurrence rate of patients with a negative resection margin (P=0.028). Older age (age >60 years), advanced stage, positive resection margin, high histological grade, and high expression of Ki-67 were significantly correlated with poor prognosis. In conclusion, the site of origin plays a role in the prognosis of ACC, in which positive resection margin and advanced stage are possible factors underlying the differences in outcomes.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Bronchial Neoplasms; Cadherins; Carcinoma, Adenoid Cystic; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Disease-Free Survival; Female; Follow-Up Studies; Humans; Ki-67 Antigen; Lacrimal Apparatus Diseases; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Nose Neoplasms; Radiotherapy, Adjuvant; Retrospective Studies; Salivary Gland Neoplasms; Survival Rate; Tracheal Neoplasms; Treatment Outcome; Young Adult

Expression of Cyclin D1 is believed to lead to progression through the G1 to S cell cycle checkpoint, and both experimental and pathological evidence suggests that overexpression of this protein may increase the risk of several cancers. The Cyclin D1 A870G polymorphism may modulate expression of the Cyclin D1 protein and is associated with the development of several types of tumor. We investigated the association between the Cyclin D1 A870G polymorphism and susceptibility to salivary gland tumors (SGTs) by PCR-RFLP in 102 Chinese SGT patients and 101 healthy controls. The frequencies of the AG (p=0.002; odds ratio (OR), 3.466) and AA (p=0.003; OR, 3.133) genotypes of Cyclin D1 were significantly higher in patients with SGT than in the healthy controls. The frequencies of these two genotypes were also significantly higher in pleomorphic adenoma (PA) patients (p=0.002; OR, 2.229), compared with the healthy controls. In addition, the expression of Cyclin D1 was found to be significantly higher in PA patients with the AA genotype, compared with PA patients with the GG genotype. Taken together, our results suggested that the Cyclin D1 A870G polymorphism is associated with an increased risk of SGTs in the Chinese population. The Cyclin D1 AA genotype not only increased the risk of PA, but also increased the expression of Cyclin D1 in this type of tumor.

Topics: Asian People; Case-Control Studies; Cyclin D1; Female; Genes, bcl-1; Genetic Predisposition to Disease; Genotype; Humans; Immunohistochemistry; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk Factors; Salivary Gland Neoplasms

Cytoplasmic and nuclear accumulation of beta-catenin in mucoepidermoid carcinoma (MEC) is frequently noted, but the mechanism is unknown.. The methylation status of adenomatous polyposis coli (APC) and secreted frizzled-related proteins (SFRPs) was examined by methylation-specific polymerase chain reaction (MSP) assay. The association of SFRP1, beta-catenin, and cyclin D1 expression in MEC was evaluated by immunohistochemical staining.. A high percentage of methylation in APC and the SFRP genes was found in MEC compared with adjacent normal tissues, in which SFRP1 (58.6%) was the most frequent methylated gene. Moreover, abundant expression of SFRP1 was noted in normal tissues, whereas reduced SFRP1 expression was detected in 71.7% (33/46) of MECs. There was significant association between methylation and reduced expression of SFRP1. Cytoplasmic/nuclear (C/N) beta-catenin and high cyclin D1 expression were found in 13/55 (23.6%) and 36/55 (65.5%) of cases, respectively. There was significant correlation between C/N beta-catenin expression and reduced SFRP1 expression (P = 0.009). In addition, SFRP1 and beta-catenin expression correlated with tumor malignancy index such as tumor grade and stage. Overall patient survival was significantly worse in patients with reduced SFRP1 and C/N beta-catenin expression (P = 0.009 and P = 0.002, respectively).. Methylation of the SFRP1 gene was the major cause of reduced SFRP1 expression. Reduced SFRP1 led to C/N accumulation of beta-catenin and was associated with tumor malignancy. Therefore, examination of SFRP1 expression and beta-catenin location could be useful predictors of tumor progression and prognosis in patients with MEC.

Topics: Adenomatous Polyposis Coli; beta Catenin; Biomarkers, Tumor; Carcinoma, Mucoepidermoid; Cell Line, Tumor; Cyclin D1; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Methylation; Neoplastic Processes; Polymerase Chain Reaction; Prognosis; Salivary Gland Neoplasms; Survival Analysis

The aim of the present study was the search of molecular alterations (oncogene amplification or protein overexpression) that could have an impact on the outcome of ACC patients. For this purpose, paraffin-embedded tissue samples of primary ACC of 24 patients were collected. Oncogenic amplification status of six targets previously described to be involved in human carcinogenesis (ERBB1, KIT, PIK3CA, CCND1, MYC and MDM2) were studied by a PCR-based semiquantitative approach. C-Kit, cyclin D1 and EGFR protein levels were immunohistochemically assessed. ERBB1, CCND1 and PIK3CA were frequent targets of oncogene amplification (67, 46 and 38%, respectively). C-Kit and cyclin D1 were overexpressed in 57 and 82%, respectively. CCND1 amplification was associated with advanced tumour stage and ERBB1 amplification to distant metastasis. ERBB1/CCND1/PIK3CA coamplification was the most consistently observed pattern (29%). The cases with this amplification pattern presented a reduced survival. This study points to the importance of ERBB1, CCND1 and PIK3CA oncogenic amplification status in ACC carcinogenesis.

Topics: Adolescent; Adult; Aged; Carcinoma, Adenoid Cystic; Cyclin D1; ErbB Receptors; Female; Gene Amplification; Genes, bcl-1; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Oncogenes; Proto-Oncogene Proteins c-kit; Salivary Gland Neoplasms; Survival Rate; Young Adult

Galectin-3 has been implicated in tumor progression of some malignancies as thyroid, prostate, and salivary gland tumors. Recently, it has been suggested that this protein may be an important mediator of the beta-catenin/Wnt pathway. Moreover, nuclear galectin-3 expression has been implicated in cell proliferation, promoting cyclin D1 activation. Thus, the present study aimed to correlate galectin-3 expression with beta-catenin and cyclin D1 expressions in adenoid cystic carcinoma (ACC) and in polymorphous low-grade adenocarcinoma (PLGA).. Fifteen formalin-fixed paraffin-embedded cases of each tumor were retrieved from the files of the Surgical Oral Pathology Service at the University of São Paulo and the proteins were analyzed by immunohistochemistry.. Adenoid cystic carcinoma showed galectin-3 immunostaining mainly in the nuclei, while PLGA revealed a positive mostly cytoplasmic reaction to galectin-3 in the largest part of tumor cells. Both tumors showed intense cytoplasmic/nuclear staining for beta-catenin in majority of cases. Cyclin D1 immunoreactivity was not detected in 14/15 PLGA and showed specific nuclear staining in 10/15 cases of ACC in more than 5% of the neoplastic cells. Cyclin D1 expression was correlated with cytoplasmic and nuclear galectin-3 expression in ACC (P < 0.05).. These results suggest that in ACC galectin-3 may play a role in cellular proliferation through cyclin D1 activation. In addition, nuclear expression of galectin-3 in ACC may be related to a more aggressive behavior of this lesion. Although beta-catenin seems to play a role in carcinogenesis in both lesions, it seems that it does not bind to galectin-3 for cyclin D1 stimulation.

Topics: Adenocarcinoma; beta Catenin; Carcinoma, Adenoid Cystic; Cell Membrane; Cell Nucleus; Cell Transformation, Neoplastic; Cyclin D1; Cytoplasm; Galectin 3; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Retrospective Studies; Salivary Gland Neoplasms; Signal Transduction; Wnt Proteins

To observe the effects of basic fibroblast growth factor (bFGF) on human adenoid cystic carcinoma ACC-2 cell line proliferation and ERK, cyclin D1/p21(waf/cip1) signaling pathways, human adenoid cystic carcinoma cells (ACC-2) were cultured and the influence of bFGF of different concentrations on cell proliferation was determined by MTT. Protein was detected by immuno-precipitation and ERK activity by using ERK agent kit. p-ERK(1/2) and down-stream cyclin D1, p21(waf/cip1) expression were detected by Western blotting and the interfering role of mitogen protein-activated kinase (MEK) suppressor U0126 in the afore-mentioned indicators was examined. MTT demonstrated ACC-2 cell proliferation was substantially enhanced by bFGF, immuno-precipitation displayed ERK activity was up-regulated by bFGF, and immuno-imprinting also showed p-ERK(1/2), cyclin D1 expression was greatly enhanced and p21(waf/cip1) expression was inhibited by bFGF. U0126 suppressed the effect of bFGF. It is concluded that bFGF can promote the proliferation of human adenoid cystic carcinoma ACC-2 cells, and its pathways are associated with the up-regulated activity and expression of p-ERK(1/2), inhibited p21waf/cip1 expression and enhanced cyclin D1 expression.

Topics: Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Salivary Gland Neoplasms; Tetrazolium Salts; Thiazoles

Adenoid cystic carcinoma (ACC) of the salivary glands exhibits persistent growth, invasion and metastasis. Chromosome 11q13 amplification is a frequent event associated with tumor progression in a number of carcinomas and is associated with poor prognosis. Two genes within the 11q13 amplicon that are overexpressed as a result of 11q13 amplification are the cell cycle regulatory protein cyclin D1 (CCND1) and cortactin (CTTN), a protein involved cell motility and invasion. To determine the expression and gene status of cyclin D1 and cortactin in ACC, we evaluated 39 ACC cases by immunohistochemistry (IHC) for cyclin D1 and cortactin expression. Amplification of CCND1 and CTTN was determined by fluorescent in situ hybridization (FISH). Cyclin D1 overexpression was present in 90% (35/39) and cortactin expression in 62% (24/39) of evaluated cases, although CCND1 and CTTN levels were elevated in only two cases (5%) as determined by FISH. Our results indicate that chromosome 11q13 amplification is uncommon in ACC, but that cyclin D1 and cortactin are frequently overexpressed and may therefore contribute to the growth and invasive potential of ACC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Adenoid Cystic; Chromosomes, Human, Pair 11; Cortactin; Cyclin D1; Female; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Neoplasm Proteins; Retrospective Studies; Salivary Gland Neoplasms

Adenoid cystic carcinoma of the salivary glands (carcinoma adenoides cysticum) is malignant epithelial tumor of rare occurrence. Tumor of this kind has among salivary glands tumors uncertain prognosis and unpredictable course. The aim of the study was to characterize the patient population and the immunohistochemical analyses (p53 protein, cyclin D1).. The examined group consisted of 30 patients with adenoid cystic carcinoma of the salivary glands. The expression of p53 protein and D1 cyclin in the tumor was evaluated and the correlation between these proteins and the organ and clinical grading was defined.. The immunohistochemical studies showed in 70% the positive staining for p53 protein and 90% for cyclin D1. There was not statistically significant difference between the advanced grading of the organic and clinical adenoid cystic carcinoma.

Topics: Carcinoma, Adenoid Cystic; Cyclin D1; Female; Gene Expression; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Salivary Gland Neoplasms; Tumor Suppressor Protein p53

Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by indolent yet relentless growth that exhibits inherent resistance to systemic chemotherapy, surgical salvage and conventional radiotherapy. We used microarray analysis to characterize gene expression changes associated with ACC. Eight ACC patient specimens were compared with normal parotid gland tissue and the ACC3 cell line. Differentially expressed genes were identified (512 total) using supervised analysis methods and functional categories assigned using OntoExpress. Genes associated with morphogenesis, neurogenesis, proliferation and apoptosis characterized ACC tumors. Genes associated with saliva production and immune response characterized normal parotid tissues while the ACC3 cell line expressed genes primarily associated with proliferation, chromosome maintenance and the cell cycle. These results demonstrate that ACC tumors express genes associated with early developmental processes including morphogenesis and neurogenesis implicating oncogenic events that result in dedifferentiation of normal salivary glands.

Topics: Adult; Apoptosis; Carcinoma, Adenoid Cystic; Cyclin D1; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, cdc; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Parotid Gland; Polymerase Chain Reaction; Salivary Gland Neoplasms; Salivation

The aims of this study were to investigate the expression levels of beta-catenin, Pin1 and cyclin D1 in salivary adenoid cystic carcinomas (SACC ) and to evaluate its clinical importance, furthermore, to elucidate whether beta-catenin expression was aberrant in SACC and whether Pin1 was involved in aberrant beta-catenin and cyclin D1 expression. The expression of Pin1, beta-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, protein and mRNA expressions were detected by western blotting and RT-PCR in four SACC cell lines. Pin1 was overexpressed in 51 cases of SACC (78%), and high levels of Pin1 expression correlated with cyclin D1 positive expression (p = 0.02). Fourteen (22%) cases showed positive immunoreactivity for beta-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, which was defined as cytoplasm/nucleus staining, among which quite evident nuclear expression of beta-catenin was detected in six cases (9%), while cyclin D1 positive expression was detected in 41 cases of SACC (63%). Reduced membranous expression of beta-catenin was detected in the cases with metastasis (11/14). Theses results suggest that Pin1 and Wnt signalling pathway are activated in SACC and may play a pivotal role in SACC carcinogenesis and metastasis.

Topics: Adult; Aged; beta Catenin; Carcinoma, Adenoid Cystic; Cell Proliferation; Cyclin D1; Female; Humans; Male; Middle Aged; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Neoplasms

To investigate the expression of Pin1, beta-catenin and cyclin D1 in salivary adenoid cystic carcinomas (SACC) and to evaluate the role of beta-catenin and Pin1 in SACC carcinogenesis.. The expressions of Pin1, beta-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, and Pin1 protein and mRNA expressions detected by Western blot and RT-PCR in four SACC cell lines.. Pin1 was overexpressed in 51 cases of ACC (78%), and 41 (63%) cases showed positive immunoreactivity for cyclin D1 protein in the nuclear fraction in tumor tissues. Fourteen (22%) cases showed positive immunoreactivity for beta-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, 6 of which exhibited quite evident expression of beta-catenin in nucleolus. The expression of membranous beta-catenin was down-regulated in most of the patients with lymph node metastasis (11/14).. The results suggest that Pin1 and beta-catenin signalling pathway were activated in SACC and might play a pivotal role in SACC carcinogenesis and metastasis.

Topics: beta Catenin; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cyclin D1; Humans; Lymphatic Metastasis; Neoplasm Invasiveness; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Salivary Gland Neoplasms

We evaluated the expression of beta-catenin, E-cadherin, and cyclin-D1 in 23 cases of adenoid cystic carcinoma (ACC) of the salivary gland. We detected beta-catenin on the cell membranes in all ACCs, but its distribution was irregular, as compared to that on normal structures. In three out of the 23 cases, beta-catenin was detected in the nuclei, as well as on cell membranes. Polymerase chain reaction (PCR) and direct sequencing revealed a missense mutation in one case in which beta-catenin had been detected in the nuclei of tumor cells. We also detected E-cadherin on cell membranes with a similar irregular distribution to that of beta-catenin. In 11 cases (almost 48%) of ACC, cyclin D1 was localized in cell nuclei but there was no correlation with the nuclear staining of the beta-catenin. Our results suggest that disturbances in the distribution of beta-catenin and E-cadherin might affect the morphology ofACC and that a small fraction of cases of ACC are characterized by a mutation in the beta-catenin gene, which is associated with the nuclear accumulation of the product of this gene but does not affect the transcription of the gene for cyclin-D1.

Topics: Base Sequence; beta Catenin; Cadherins; Carcinoma, Adenoid Cystic; Cell Nucleus; Cyclin D1; Cytoskeletal Proteins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Molecular Sequence Data; Mutation; Salivary Gland Neoplasms; Trans-Activators

To observe the expression of cyclin D1 in human adnoid cystic carcinoma and its correlation with clinical characters.. The expression of cycline D1 was evaluated with immunohistochemical method in forty-one cases of human adnoid cystic carcinoma, 15 cases of PA and 12 cases of normal salivary gland tissue.. The expression of cyclin D1 in normal tissue was negative, significantly different from PA and ACC (P < 0.05). The expression level of PA was significantly lower than ACC (P < 0.05). High expression of cyclin D1 was correlated with clinical stage and histological classification (P < 0.05), but not with sex, age, tumor site, recurrence, metastasis.. High expression of cyclin D1 promotes the formation and development of ACC.

Topics: Carcinoma; Carcinoma, Adenoid Cystic; Cyclin D1; Female; Humans; Middle Aged; Salivary Gland Neoplasms

Salivary gland acinic cell carcinoma (ACC) is a relatively rare neoplasm, and limited information is available regarding its molecular pathogenesis. Because the deregulation of Rb pathway is common to most human tumors, we immunohistochemically investigated the expression of Rb pathway-related proteins, including Rb, Rb proteins phosphorylated at serine 780 and 795 (pRb-S780 and pRb-S795, respectively), cyclin D1, and p16INK4a in 18 cases of ACC. The expression of topoisomerase II-alpha and Ki-67 was also examined to evaluate cell proliferation. All the ACCs exhibited substantial numbers of positive cells against Rb antibody that recognizes both unphosphorylated and phosphorylated Rb proteins. The numbers of positive cells for pRb-S795 and cyclin D1 significantly increased in ACCs as compared with normal salivary glands. Double immunofluorescent staining demonstrated that pRb-S795 was colocalized with cyclin D1 in most tumor cells. However, neither significant change of the expression of Rb protein phosphorylated at serine 780 nor its colocalization with cyclin D1 was observed. The loss of p16INK4a is infrequent, but its expression was correlated with phosphorylated Rb proteins. Our results suggest that serine 795 but not serine 780 is the preferred phosphorylation site induced by cyclin D1. This phosphorylation appeared to be critical for inactivation of Rb-mediated growth suppression and may play an important role in the pathogenesis of ACC.

Topics: Adolescent; Adult; Aged; Antigens, Neoplasm; Carcinoma, Acinar Cell; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; DNA Topoisomerases, Type II; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Retinoblastoma Protein; Salivary Gland Neoplasms

Adenoid cystic carcinoma is a malignant tumor of salivary gland origin. It tends to grow slowly, but shows frequent recurrence and metastasis. Cyclin D1, a cell-cycle regulation protein, has been reported to be overexpressed in various types of cancer and to correlate with poor survival of the patients. However, the prognostic significance of cyclin D1 expression in ACC of the salivary glands has not yet been determined. To evaluate the role of cyclin D1 in the biological regulation of ACC, we constitutively expressed an antisense cyclin D1 complementary DNA (cDNA) in an established ACC cell line that exhibits high endogenous expression of cyclin D1. The effect of cyclin D1 expression on in vitro cell growth and cell cycle were examined. In addition, we also examined the immunohistochemical expression of cyclin D1 protein in 31 cases of ACC of the salivary gland and correlated its expression with proliferative activity or prognosis. There were no significant differences of the in vitro growth and in the percentage of the total cell population in the G1 phase and S phase between antisense cyclin D1 clones and control clones. Thirty-two percent of tumors derived from surgical specimens examined were immunohistochemically positive for cyclin D1 protein. No association was found between cyclin D1 expression and cell proliferation or the clinical outcome of the patients. It is concluded that cyclin D1 overexpression alone does not induce a marked increase in the proliferative activity of ACC cells and that expression of this protein is not linked to poor prognosis in adenoid cystic carcinoma of the salivary gland.

Topics: Actins; Adult; Aged; Blotting, Western; Carcinoma, Adenoid Cystic; Cell Proliferation; Cyclin D1; DNA, Antisense; DNA, Complementary; Female; Flow Cytometry; Genes, bcl-1; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Salivary Gland Neoplasms

Adenoid cystic carcinoma (ACC) is a tumour of epithelial origin that represents the most common malignant neoplasm of the minor salivary glands. However, little is known about the genes involved in the development and progression of this tumour. Cyclin D1 gene (CCND1) plays a key role in the control of the cell cycle, and its amplification is described in numerous cancers. The aim of this study is to determine the amplification of the CCND1 gene in the ACC of the minor salivary glands.. A retrospective study was performed on 12 patients with ACC of the head and neck. The amplification of the CCND1 was determined using multiple PCR.. Amplification of the CCND1 was found in 4 patients (33.3%). No correlation was found between CCND1 amplification and clinicopathological parameters, although disease-free survival was diminished in patients with amplification.. Our study demonstrates for the first time the amplification of the CCND1 gene in ACC. We have found an amplification rate similar to others neoplasms. CCND1 amplification seems to be associated with a poorer prognosis in these tumours, although this needs to be confirmed in larger studies.

Topics: Adult; Aged; Carcinoma, Adenoid Cystic; Cyclin D1; Female; Gene Amplification; Humans; Male; Middle Aged; Salivary Gland Neoplasms

Transgenic mice expressing specific oncogenes usually develop tumors in a stochastic fashion suggesting that tumor progression is a multi-step process. To gain further understanding of the interactions between oncogenes and tumor suppressor genes during tumorigenesis, we have crossed a transgenic strain (TG.NK) carrying an activated c-neu oncogene driven by the MMTV enhancer/promoter with p53-deficient mice. c-neu transgenic mice have stochastic breast tumor formation and normal appearing salivary glands. However, c-neu mice heterozygous for a p53 deletion develop parotid gland tumors and loose their wild type p53 allele. c-neu mice with a homozygous p53 deletion have increased rates of parotid tumor onset suggesting that inactivation of p53 is required and sufficient for parotid gland transformation in the presence of activated c-neu. In contrast to the dramatic effect of p53 in parotid gland transformation, p53 loss has little effect on the rate or stochastic appearance of mammary tumors. In addition, p53 loss was accompanied by the down regulation of p21 in parotid gland tumors but not breast tumors. The parotid gland tumors were aneuploid and demonstrated increased levels of Cyclin D1 expression. These observations suggest that in c-neu transgenic mice, p53 alterations have differential tissue effects and may be influenced by the tissue specific expression of genes influencing p53 activity.

Topics: Aneuploidy; Animals; Cell Transformation, Neoplastic; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Genes, p53; Loss of Heterozygosity; Male; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Parotid Neoplasms; Salivary Gland Neoplasms; Salivary Glands; Stochastic Processes; Tissue Distribution; Tumor Suppressor Protein p53

The diagnosis of polymorphous low-grade adenocarcinoma (PLGA) of salivary glands remains difficult for general surgical pathologists. In an effort to understand the morphological heterogeneity of these neoplasms and facilitate their recognition we reviewed the architectural patterns, cell differentiation and immunohistochemical features of 17 case of PLGA.. There were 11 females and six males with a mean age of 58 years. Twelve tumours were located in the palate, two in the posterior third of the tongue, and one each in the upper lip, buccal mucosa and retromolar triangle. Two patients presented with neck metastases. The mean tumour size was 20 mm (range 6-50 mm). The tumour cells were arranged in five architectural patterns: tubules and small duct-like structures; cords and trabeculae; solid nests; cribriform areas and papillae. Twelve (71%) cases were composed of a combination of tubules and small duct-like structures, cords and trabeculae, and solid nests. Cribriform areas with pseudoluminal spaces were seen in six (35%) cases. A focal papillary pattern was evident in three cases and constituted 40% of the tumour in one. Perineural invasion was seen in 13 cases (76%). All cases studied were positive for CAM5.2, 34BE12, vimentin and S100 protein and showed overexpression of bcl-2 protein. Rb protein was present in 13 cases whereas p53 expression was absent in all cases. The average proliferation index (PI) was 7% (range 1-17%). Three patients developed local recurrences with cervical lymph node metastases but no patient died as result of tumour. No morphological features were found to be prognostic for the development of local recurrences or lymph nodes metastases.. PLGA is a distinctive neoplasm of salivary glands formed by luminal and nonluminal tumour cells with limited patterns of architectural differentiation. The relative proportion of these cells seems to play a significant role in the morphogenesis of these tumours. The overexpression of the bcl-2 protein and the low PI suggest that inhibition of programmed cell death may be involved in the oncogenesis of PLGA.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Cell Differentiation; Cyclin D1; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein; S100 Proteins; Salivary Gland Neoplasms; Salivary Glands, Minor