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1.
Int J Cancer ; 134(9): 2108-17, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24127203

ABSTRACT

Human papillomavirus (HPV) is a risk factor for the development of benign and malignant mucosal head and neck lesions. P16(INK4A) is often used as a surrogate marker for HPV-infection, although there is still controversy with respect its reliability. Our aim was to determine if p16(INK4A) overexpression can accurately predict both high-risk and low-risk-HPV-presence in (pre)malignant and benign head and neck lesions. P16(INK4A) immunohistochemistry was performed on paraffin-embedded tissue sections of 162 oropharyngeal squamous cell carcinomas (OPSCC), 14 tonsillar and 23 laryngeal dysplasias, and 20 tonsillar and 27 laryngeal papillomas. PCR, enzyme-immunoassay and FISH analysis were used to assess HPV-presence and type. Of the 162 OPSCC and 14 tonsillar dysplasias, 51 (31%) and 10 (71%) were HPV16-positive, respectively. All tonsillar papillomas were HPV-negative and four laryngeal dysplasias and 26 laryngeal papillomas were positive for HPV6 or -11. P16(INK4A) immunohistochemistry revealed a strong nuclear and cytoplasmic staining in 50 out of 51 HPV16-positive and 5 out of 111 HPV-negative OPSCC (p < 0.0001) and in all HPV16-positive tonsillar dysplasias, whereas highly variable staining patterns were detected in the papillomas and laryngeal dysplasias, irrespective of the HPV-status. In addition, the latter lesions generally showed a higher nuclear than cytoplasmic p16(INK4A) immunostaining intensity. In conclusion, our data show that strong nuclear and cytoplasmic p16(INK4A) overexpression is a reliable surrogate indicator for HPV16 in OPSCC and (adjacent) dysplasias. For HPV6 or -11-positive and HPV-negative benign and premalignant lesions of the tonsil and larynx, however, p16(INK4A) immunostaining is highly variable and cannot be recommended to predict HPV-presence.


Subject(s)
Carcinoma, Squamous Cell/virology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Head and Neck Neoplasms/virology , Oropharyngeal Neoplasms/virology , Papilloma/virology , Papillomavirus Infections/diagnosis , Precancerous Conditions/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/metabolism , Child , Child, Preschool , Female , Head and Neck Neoplasms/metabolism , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Infant , Laryngeal Neoplasms/metabolism , Laryngeal Neoplasms/virology , Male , Middle Aged , Oropharyngeal Neoplasms/metabolism , Papilloma/metabolism , Papillomavirus Infections/complications , Precancerous Conditions/metabolism , Precancerous Conditions/virology , Risk Factors , Squamous Cell Carcinoma of Head and Neck , Young Adult
3.
Int J Cancer ; 132(8): 1781-9, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-22987500

ABSTRACT

Tonsillar squamous cell carcinoma (TSCC) is frequently associated with human papillomavirus (HPV) and chromosome instability. Data from cellular model systems are, however, controversial concerning a relation between HPV and chromosome instability development. Here we studied this association in 77 primary TSCC with known clinical outcome and cell cycle protein expression profiles. Thirty-two tumors (42%) showed HPV16-integration. All 77 cases were analyzed by fluorescence in situ hybridization using chromosome 1- and 7-specific centromere DNA probes to detect chromosome instability, indicated by the presence of chromosome imbalances and/or polyploidization for these chromosomes. In addition, eight HPV-positive dysplasias, seven of which were adjacent to a carcinoma, were analyzed. Disomy for chromosome 1 and 7 was present in 29 out of 77 TSCC (38%), of which 19 were HPV16-positive (p = 0.002). Aneusomy was observed in the remaining 48 TSCC, of which 13 were HPV-positive. Aneusomies correlated significantly with tobacco- and alcohol consumption (p = 0.001 and p = 0.016, respectively) and a higher T-stage (p = 0.018). Both HPV-positivity and chromosome disomy were significantly associated with a favorable disease-free survival (p = 0.001 and p = 0.025, respectively). Particularly in the HPV16-positive group chromosome instability is a very strong indicator for an unfavorable prognosis (p = 0.032). In the dysplasias an identical HPV and chromosome copy number status was identified as in the adjacent tumors. We conclude that HPV-positive TSCC and their precursor lesions are more often genetically stable than HPV-negative lesions and that these tumors are associated with a favorable prognosis. Chromosome instability is an indicator for unfavorable prognosis, particularly in the HPV-positive patient group.


Subject(s)
Carcinoma, Squamous Cell/genetics , Chromosomal Instability , Human papillomavirus 16/genetics , Tonsillar Neoplasms/genetics , Virus Integration , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , DNA Probes , Humans , In Situ Hybridization, Fluorescence , Prognosis , Tonsillar Neoplasms/pathology , Tonsillar Neoplasms/virology
4.
Laryngoscope ; 119(10): 1951-7, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19650127

ABSTRACT

OBJECTIVES/HYPOTHESIS: Assessment of the prognostic value of nodal status in relation to human papillomavirus (HPV) status and the various treatment modalities in tonsillar squamous cell carcinomas (TSCC). STUDY DESIGN: Retrospective 5-year survival analysis. METHODS: A 5-year follow-up of disease-free, disease-specific, and overall survival in a group of 81 patients with TSCC was conducted. The nodal status and integration of HPV-DNA in the genome (detected with fluorescence in situ hybridization) as prognostic indicators were examined while correcting for other clinical parameters (smoking habits, alcohol consumption, treatment modality, differentiation, TNM classification). RESULTS: Of TSCCs, 41% were positive for HPV type 16. In these TSCCs, the primary tumor was significantly smaller when compared to HVP-negative TSCCs (P = .04), whereas the percentage of cases with cervical metastases was identical. In the total population, it was not nodal involvement, but rather HPV manifestation, which was related to patient prognosis. Within the treatment modalities (surgery combined with radiotherapy and radiotherapy alone), neither nodal status nor HPV were prognostic indicators. CONCLUSIONS: Since a substantial percentage of TSCCs are HPV-positive and metastasizes to cervical lymph nodes in less advanced primary tumors, the N status is an unreliable prognostic indicator in TSCCs. HPV is only prognostically relevant in the total tumor population, but loses its value within patient groups receiving a single treatment modality. The value of HPV for prognosis of patients with TSCC requires further study.


Subject(s)
Alphapapillomavirus/isolation & purification , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/virology , Tonsillar Neoplasms/mortality , Tonsillar Neoplasms/virology , Adult , Aged , Aged, 80 and over , Alcohol Drinking/epidemiology , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/pathology , DNA, Viral/analysis , Disease-Free Survival , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Prognosis , Retrospective Studies , Risk Factors , Smoking/epidemiology , Tonsillar Neoplasms/epidemiology , Tonsillar Neoplasms/pathology
5.
Mod Pathol ; 22(5): 686-98, 2009 May.
Article in English | MEDLINE | ID: mdl-19305381

ABSTRACT

Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/metabolism , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Papillomavirus Infections/metabolism , Tonsillar Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/virology , Cell Cycle Proteins/biosynthesis , Cyclin D1/biosynthesis , Female , Gene Expression , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Papillomaviridae , Papillomavirus Infections/mortality , Prognosis , Retinoblastoma Protein/biosynthesis , Smoking/adverse effects , Tonsillar Neoplasms/mortality , Tonsillar Neoplasms/virology , Tumor Suppressor Protein p14ARF/biosynthesis
6.
Clin Cancer Res ; 15(5): 1779-86, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19223504

ABSTRACT

PURPOSE: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer. EXPERIMENTAL DESIGN: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16(INK4A) immunostaining. The results were correlated with HPV status and clinical data from patients. RESULTS: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P=0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P=0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P=0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P=0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P=0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P=0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P=0.008; disease-free survival, P=0.01) and none of these patients had a tumor recurrence. CONCLUSIONS: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.


Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Profiling , Human papillomavirus 16/genetics , Oropharyngeal Neoplasms/genetics , Oropharyngeal Neoplasms/metabolism , Alcohol Drinking , Carcinoma, Squamous Cell/virology , Chromosome Aberrations , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 3/genetics , Comparative Genomic Hybridization , Feasibility Studies , Gene Dosage , Human papillomavirus 16/isolation & purification , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Neoplasm Staging , Oropharyngeal Neoplasms/virology , Papillomavirus Infections/genetics , Papillomavirus Infections/metabolism , Papillomavirus Infections/virology , Polymerase Chain Reaction , Prognosis , Risk Factors , Smoking , Survival Rate
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