cyclin-d1 and Hypopharyngeal-Neoplasms

Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q-PIK3CA, TP63; 11q13.3-CCND1, ANO1) in tumor DNA recovered from HPSCC (n = 48) and OPSCC (n = 52) patients. Associations between copy number gain, patient demographics, HPV/p16INK4a status and pathological stage were examined. HPV/p16 prevalence in HPSCC and OPSCC groups was 2.1% and 46.0%, respectively. HPSCCs had frequent gains of CCND1 (56.3%) and ANO1 (56.3%) but few gains of PIK3CA (6.3%). By contrast, OPSCCs had significantly fewer CCND1 (23.1%) and ANO1 (17.3%) gains, and significantly more PIK3CA (26.9%) gains. A mutually exclusive relationship between HPV/p16 and 11q13.3 gains was observed in OPSCCs, while PIK3CA and TP63 gains were similar across HPV-associated and smoking/alcohol-associated patients. ANO1 gain was significantly linked to tumor pathology in HPSCC, associating with nodal metastasis and smaller and less invasive tumors at presentation (P = 0.010). Our results provide a convincing link between a specific molecular change and disease phenotype that appears unique to our HPSCC population, supporting a model of 11q13.3 in promoting metastatic disease progression in HNSCC, and suggest a role for ANO1 as a molecular marker of metastatic disease. © 2016 Wiley Periodicals, Inc.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; Chromosomes, Human, Pair 11; Class I Phosphatidylinositol 3-Kinases; Cyclin D1; DNA Copy Number Variations; Female; Follow-Up Studies; Humans; Hypopharyngeal Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oropharyngeal Neoplasms; Papillomaviridae; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Prognosis; Survival Rate

P16 and cyclin-D1 are cell cycle proteins commonly dysregulated in head and neck carcinoma. We assessed their expression, clinicopathological variables, and overall survival (OS) in oropharyngeal and hypopharyngeal squamous cell carcinoma (SCC).. Clinical characteristics and p16 and cyclin-D1 expression were evaluated in 101 patients with oropharyngeal SCC and 75 patients with hypopharyngeal SCC. Associations with OS were assessed using Cox regression and Kaplan-Meier analysis.. Compared to oropharyngeal SCC, patients with hypopharyngeal SCC were older, men, ever-smokers with higher mean Charlson Comorbidity Index (CCI), lower p16 expression, and poorer median OS (24.8 vs 62.3 months; p < .01). In oropharyngeal SCC, CCI (p < .001), cyclin-D1 (hazard ratio [HR] = 3.55; p = .007), current smoking (HR = 5.72; p = .004), and former smoking (HR = 4.12; p = .035) were independently associated with OS. In hypopharyngeal SCC, only nodal and Eastern Cooperative Oncology Group status were associated with OS.. In oropharyngeal SCC, cyclin-D1 expression is correlated with survival, whereas smoking status and CCI may allow further stratification of outcome.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Biopsy, Needle; Carcinoma, Squamous Cell; Cohort Studies; Cyclin D1; Databases, Factual; Disease-Free Survival; Female; Human papillomavirus 16; Humans; Hypopharyngeal Neoplasms; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Oropharyngeal Neoplasms; Prognosis; Proportional Hazards Models; Retrospective Studies; Singapore; Survival Analysis

Head and neck squamous cell carcinomas (HNSCCs) are characterized by marked heterogeneity in their biological behavior and response to treatment. Our goal was the identification of biomarkers that can be used to predict response to chemotherapy in these patients.. The expression of EGFR, p53, Cyclin D1, p16, p21, p27, p-AKT, HIF-1α, Caspase 3 and BCL2 was analyzed by immunohistochemistry in 41 primary laryngeal/hypopharyngeal squamous cell carcinomas of patients that received induction chemotherapy (cisplatin and 5-fluorouracil) as part of their treatment.. Positive expression of p27 and BCL2 had a significant predictive value for chemotherapy response in univariate analysis. The combination of both proteins was not superior in predicting the response to chemotherapy. Furthermore, p27 expression was the only significant predictor of chemotherapy response in multivariate analysis (P=0.015).. p27 Expression may serve as predictive biomarker of response to induction chemotherapy in HNSCC patients.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Caspase 3; Cisplatin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21; ErbB Receptors; Female; Fluorouracil; Humans; Hypopharyngeal Neoplasms; Hypoxia-Inducible Factor 1, alpha Subunit; Laryngeal Neoplasms; Male; Middle Aged; Neoplasm Proteins; Prognosis; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

To study the expressions of Cyclin D1 and p16 proteins in hypopharyngeal squamous cell carcinoma and their clinical significance.. Immunohistochemical technology (P-V) was applied to detect the expression of Cyclin D1 and p16 in 36 cases of hypopharyngeal squamous cell carcinoma and 10 cases of normal epithelium.. (1) The expression of cyclin D1 in the tumorous cell was significantly higher than that in normal epithelium (P < 0.05). The expression of p16 in the tumorous cell was significantly lower than that in normal epithelium (P < 0.05); (2) The positive rate of Cyclin D1 was significantly correlated with clinical stage and cervical lymph node metastases (P < 0.05). The positive rate of p16 was correlated with cervical lymph node metastases (P < 0.05). The positive rates of Cyclin D1 and p16 were not correlated with the gender, age, tumor size, primary lesion and cell differentiation (P > 0.05); (3) There was correlation between the expression of Cyclin D1 and the expression of p16 (r(s) = -0.420, P < 0.05).. The over-expression of Cyclin D1 and the under-expression of p16 may play a significant role in the occurrence incidence and development of hypopharyngeal squamous cell carcinoma, and may be important indicators for cervical lymph node metastases.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Case-Control Studies; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Female; Humans; Hypopharyngeal Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Prognosis

To study the relation ship between Cyclin expression and the biological behavior in 53 cases of hypopharyngeal squamous cell carcinoma.. Immunohistochemical (sp). method was used to detect the expression of cyclin D in 53 cases of hypopharyngeal squamous cell carcinoma and 11 cases of normal adjacent epithelium.. Positive expression for Cyclin D1 in hypopharyngeal squamous cell carcinoma was found in nuclear. The expression of cyclin D1 in the tumorous cell was significant hig her than in normal epithelium. Cyclin D1 expression was related to T grade and primary site, which correlation coefficient were 0.345 and -0.386 respectively. The highest positive rate of Cyclin D1 expression was in pyriform sinus.. Cyclin D1 expression was related to T grade and primary site positively.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Cyclin D1; Female; Humans; Hypopharyngeal Neoplasms; Male; Middle Aged

The prognostic divergence of laryngeal and hypopharyngeal carcinomas is well known. Hypopharyngeal tumors are characterized by frequent metastasis formation and local recurrence, which is the source of the unfavorable prognosis of this subtype. The aim of this study was to define chromosomal alterations associated with the aggressive behavior of hypopharyngeal tumors.. Twenty-nine head and neck squamous cell carcinomas (larynx n = 14 and hypopharynx n = 15) were analyzed by comparative genomic hybridization (CGH). Fluorescence in situ hybridization (FISH) was used to validate the CGH data and to compare the amplification pattern of the most frequently altered gene (cyclin-D1, CCND1) located on 11q13.. The average number of genetic alterations was significantly higher in the hypopharyngeal tumors (P = 0.02). A good correlation of FISH and CGH data were seen. Gains on 11q13 were present in both subtypes, whereas amplification of CCND1 was associated with the aggressive phenotype by FISH. Chromosomal alteration, which was rarely detected in hypopharyngeal tumors but was observed in more than 50% of laryngeal carcinomas, was 8q gain.. Our CGH and FISH data show that head and neck squamous cell carcinomas contain complex cytogenetic alterations and further support the hypothesis that different molecular pathways are responsible for the progression of differently localized tumors of the upper aerodigestive tract.

Topics: Aged; Chromosome Aberrations; Chromosomes, Human, Pair 11; Cyclin D1; Female; Gene Dosage; Humans; Hypopharyngeal Neoplasms; In Situ Hybridization, Fluorescence; Laryngeal Neoplasms; Male; Middle Aged; Nucleic Acid Hybridization

Squamous cell carcinoma of the upper aerodigestive tract (UADT) is associated with environmental factors, especially tobacco and alcohol consumption. Genetic factors, including cyclin D1 (CCND1) polymorphism have been suggested to play an important role in tumorigenesis and progression of UADT cancer. To investigate the relationship between CCND1 polymorphism on susceptibility for UADT cancers, 147 cancer and 135 non-cancer subjects were included in this study. CCND1 genotype at codon 242(G870A) in exon 4 was undertaken using denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. Significant odds ratio (OR) of the AA+GA genotypes [OR=7.5 (95% CI: 1.4-39.7)] was observed in non-drinkers but for non-smokers a non-significant [OR=5.4 (95% CI: 0.9-31.4)] was found in the adjusted model. These results suggest that allele A may be a risk factor for UADT cancer, especially in non-alcoholics. However, further epidemiological studies are needed to establish the exact role of CCND1 polymorphism and the development of UADT cancers.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alleles; Carcinoma, Squamous Cell; Cyclin D1; Female; Genotype; Head and Neck Neoplasms; Humans; Hypopharyngeal Neoplasms; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Oropharyngeal Neoplasms; Polymorphism, Genetic; Risk Factors

Alterations of cell cycle proteins contribute to the development and biological behaviour of malignant tumours. We evaluated the distribution and prognostic significance of immunohistochemically detected proteins p53, p21, Rb, and cyclin D1 in 101 laryngeal and hypopharyngeal squamous cell carcinomas (SCC) and adjacent epithelial hyperplastic lesions (EHL). Protein expression was correlated with tumour grade and stage. Varying patterns of protein expression were found in SCC. A significant correlation (p<0.05) was found between Rb expression and tumour grade. Different grades of EHL exhibited randomly distributed p53 and cyclin D1 positive cell clusters with no association to the pattern of their expression in SCC. Our study demonstrated derailment of cell cycle regulation in almost all cases of SCC of the larynx and hypopharynx. However, only cyclin D1 expression had an independent prognostic value for cancer-specific survival. The results also suggest that Rb gene inactivation, although rare, might be more important in the development of SCC than previously thought.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Enzyme Inhibitors; Female; Humans; Hyperplasia; Hypopharyngeal Neoplasms; Hypopharynx; Immunohistochemistry; Laryngeal Neoplasms; Larynx; Male; Middle Aged; Prognosis; Respiratory Mucosa; Retinoblastoma Protein; Tumor Suppressor Protein p53

The aim of this retrospective study was to identify reliable predictive factors for local control of hypopharyngeal cancer (HPC) treated by radiotherapy.. A cohort of 38 patients with HPC treated by radical radiotherapy at the National Cancer Center Hospital East between 1992 and 1999 were selected as subjects for the present study. Paraffin-embedded pre-therapy biopsy specimens from these patients were used for immunostaining to evaluate the relationships between local tumor control and expression of the following previously reported predictive factors for local recurrence of head and neck cancer treated by radiotherapy: Ki-67, Cyclin D1, CDC25B, VEGF, p53, Bax and Bcl-2. The predictive power of microvessel density (MVD) in biopsy specimens and of clinicopathologic factors (age, gender and clinical tumor-node-metastasis stage) was also statistically analyzed.. Twenty-five patients developed tumor recurrence at the primary site. Univariate analysis indicated better local control of tumors with high microvessel density [MVD >or= median (39 vessels/field)] than with low MVD (< median, P = 0.042). There were no significant associations between local control and expression of Ki-67 (P = 0.467), Bcl-2 (P = 0.127), Bax (P = 0.242 ), p53 (P = 0.262), Cyclin D1 (P = 0.245), CDC25B (P = 0.511) or VEGF (P = 0.496). Clinicopathologic factors were also demonstrated to have no significant influence on local control (age, P = 0.974; gender, P = 0.372; T factor, P = 0.602; N factor, P = 0.530; Stage, P = 0.499).. Microvessel density in biopsy specimens was closely correlated with local control of HPC treated by radiotherapy.

Topics: Adult; Aged; Aged, 80 and over; bcl-2-Associated X Protein; Biopsy; cdc25 Phosphatases; Cell Cycle Proteins; Cohort Studies; Cyclin D1; Dose Fractionation, Radiation; Female; Humans; Hypopharyngeal Neoplasms; Hypopharynx; Ki-67 Antigen; Male; Middle Aged; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A

Multiple primary upper aerodigestive tract carcinomas can occur in up to 15% of patients. We have shown previously that half of the patients with multiple upper aerodigestive tract squamous cell carcinomas are initially seen with synchronous tumors. Most metachronous squamous cell carcinomas become manifest within 3 years.. To examine the expression of 2 proteins-cyclin D1 and p53--in an attempt to predict the occurrence of multiple primary malignant neoplasms (MPs).. Monoclonal antibodies to cyclin D1 (DCS-6 [dilution, 1:50]. Novocastra Laboratories Ltd, Newcastle, England) and p53 (DO-7 [dilution, 1-100], Dako Corp, Carpinteria, Calif) proteins were used. Resection specimens from a total of 47 patients, 12 patients with MP and 35 patients with nonmultiple primary malignant neoplasms, were analyzed. Those in the nonmultiple primary malignant neoplasm group had longer than 3 years' follow-up to ascertain the absence of MP.. Tumor overexpression of cyclin D1 was significantly associated with the development of MP (P<.01). Tumor overexpression of p53 was also frequent in patients with MP although statistical significance was not achieved. The combination of these 2 parameters was an even greater predictor of MP (P<.001).. Overexpression of cyclin D1 and p53 proteins was highly correlated with the development of MP. Additional studies are necessary to confirm this finding. Immunohistochemical evaluation of primary squamous cell carcinomas for cyclin D1 and p53 overexpression may become an important fact of surgical pathologic reporting for primary upper aerodigestive tract squamous cell carcinomas.

Topics: Carcinoma, Squamous Cell; Cyclin D1; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Hypopharyngeal Neoplasms; Neoplasms, Multiple Primary; Predictive Value of Tests; Prognosis; Tumor Suppressor Protein p53

Hypopharyngeal carcinoma (HPC) has a poor prognosis. We investigated the expression of cyclin D1 in 34 advanced HPCs, and the value of cyclin D1 expression was evaluated as a predictive marker in terms of the prognosis of HPC, compared with other clinical factors. Using immunohistochemical staining, 20 of 34 patients showed positive immunoreactivity for cyclin D1. The statistical trend of the survival rate was lower in the cyclin D1-positive patients than in the cyclin D-negative ones (p = 0.0805). The predictive factors for the survival rate were effectiveness of neo-adjuvant chemotherapy (F = 8.698) (p = 0.0066), cyclin D1 expression (F = 6.244) (p = 0.0191) and N classification (F = 5.037) (p = 0.0335). The cyclin D1-positive patients had approximately four-fold higher mortality than the cyclin D1-negative ones. These data indicate that the expression of cyclin D1, in advanced patients with hypopharyngeal carcinoma is a useful marker for prognosis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma; Cyclin D1; Female; Humans; Hypopharyngeal Neoplasms; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Survival Rate

Hypopharyngeal squamous cell carcinomas (HPCS) are associated with an extremely poor prognosis. Generally, conventional clinicopathologic factors have only limited value as prognostic factors for this malignancy. It is therefore clinically important to identify new prognostic factors that accurately reflect the biologic aggressiveness of this malignancy. The amplification and overexpression of the cyclin D1 protooncogene have been reported in a variety of malignancies, and are thought to be related to tumor progression. Based on this phenomenon, the authors immunohistochemically evaluated overexpression of the cyclin D1 gene in 42 cases of primary HPCS. In addition, the immunohistochemical staining of the proliferation marker MIB-1 (Ki-67 antibody) was also performed.. Formalin fixed, paraffin embedded biopsy specimens obtained prior to treatment were examined. Cyclin D1 and Ki-67 were detected using monoclonal antibodies by means of the streptavidin-biotin method. The relationship between cyclin D1 overexpression and the stage, histologic grade, presence of lymph node metastases, proliferation index, and survival was then statistically analyzed. The correlation between the proliferation index, other clinicopathologic factors, and survival was also evaluated.. Twenty-three (54.8%) HPCS specimens showed a 20% or greater immunoreactivity for cyclin D1. Cyclin D1 overexpression was related to cervical lymph node metastases (P = 0.037) but not to clinical stage, histologic grade, or the proliferation index. Cyclin D1 negative tumors were associated with a significantly better prognosis (P = 0.023), particularly in patients who underwent multimodality treatment. Finally, the MIB-1 labeling index showed no correlation with either the clinicopathologic parameters or overall survival.. Based on these findings, cyclin D1 immunohistochemical staining is considered to be useful, not only as a prognostic factor for HPCS, but also as a means of determining the optimum treatment for each individual patient. Conversely, the MIB-1 labeling index appears to have no clinical significance in HPCS.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cyclin D1; Cyclins; Female; Humans; Hypopharyngeal Neoplasms; Immunohistochemistry; Ki-67 Antigen; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins; Prognosis; Survival Rate