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      Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States

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          Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.

          Patients and Methods

          HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses.


          HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020.


          Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.

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          Most cited references 23

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          Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States.

          To investigate the impact of human papillomavirus (HPV) on the epidemiology of oral squamous cell carcinomas (OSCCs) in the United States, we assessed differences in patient characteristics, incidence, and survival between potentially HPV-related and HPV-unrelated OSCC sites. Data from nine Surveillance, Epidemiology, and End Results program registries (1973 to 2004) were used to classify OSCCs by anatomic site as potentially HPV-related (n = 17,625) or HPV-unrelated (n = 28,144). Joinpoint regression and age-period-cohort models were used to assess incidence trends. Life-table analyses were used to compare 2-year overall survival for HPV-related and HPV-unrelated OSCCs. HPV-related OSCCs were diagnosed at younger ages than HPV-unrelated OSCCs (mean ages at diagnosis, 61.0 and 63.8 years, respectively; P < .001). Incidence increased significantly for HPV-related OSCC from 1973 to 2004 (annual percentage change [APC] = 0.80; P < .001), particularly among white men and at younger ages. By contrast, incidence for HPV-unrelated OSCC was stable through 1982 (APC = 0.82; P = .186) and declined significantly during 1983 to 2004 (APC = -1.85; P < .001). When treated with radiation, improvements in 2-year survival across calendar periods were more pronounced for HPV-related OSCCs (absolute increase in survival from 1973 through 1982 to 1993 through 2004 for localized, regional, and distant stages = 9.9%, 23.1%, and 18.6%, respectively) than HPV-unrelated OSCCs (5.6%, 3.1%, and 9.9%, respectively). During 1993 to 2004, for all stages treated with radiation, patients with HPV-related OSCCs had significantly higher survival rates than those with HPV-unrelated OSCCs. The proportion of OSCCs that are potentially HPV-related increased in the United States from 1973 to 2004, perhaps as a result of changing sexual behaviors. Recent improvements in survival with radiotherapy may be due in part to a shift in the etiology of OSCCs.
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            Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States.

            Herpes simplex virus type 1 (HSV-1) and type 2 are common infections worldwide. Herpes simplex virus type 2 (HSV-2) is the cause of most genital herpes and is almost always sexually transmitted. In contrast, HSV-1 is usually transmitted during childhood via nonsexual contacts. Preexisting HSV-1 antibodies can alleviate clinical manifestations of subsequently acquired HSV-2. Furthermore, HSV-1 has become an important cause of genital herpes in some developed countries. To examine trends in HSV-1 and HSV-2 seroprevalence in the United States in 1999-2004 compared with 1988-1994. Cross-sectional, nationally representative surveys (US National Health and Nutrition Examination Surveys [NHANES]), were used to compare national seroprevalence estimates from 1999-2004 with those from 1988-1994, and changes in HSV-1 and HSV-2 seroprevalence since 1976-1980 were reviewed. Persons aged 14 to 49 years were included in these analyses. Seroprevalence of HSV-1 and HSV-2 antibodies based on results from type-specific immunodot assays; diagnosis of genital herpes. The overall age-adjusted HSV-2 seroprevalence was 17.0% (95% confidence interval [CI], 15.8%-18.3%) in 1999-2004 and 21.0% (95% CI, 19.1%-23.1%) in 1988-1994, a relative decrease of 19.0% between the 2 surveys (95% CI, -28.6% to -9.5%; P<.001). Decreases in HSV-2 seroprevalence were especially concentrated in persons aged 14 to 19 years between 1988 and 2004. In adolescents aged 17 to 19 years and young adults, the decreases in HSV-2 seroprevalence were significant even after adjusting for changes in sexual behaviors. Among those infected with HSV-2, the percentage who reported having been diagnosed with genital herpes was statistically different (14.3% in 1999-2004 and 9.9% in 1988-1994; P = .02). Seroprevalence of HSV-1 decreased from 62.0% (95% CI, 59.6%-64.6%) in 1988-1994 to 57.7% (95% CI, 55.9%-59.5%) in 1999-2004, a relative decrease of 6.9% between the 2 surveys (95% CI, -11.6% to -2.3%; P = .006). Among persons infected with HSV-1 but not with HSV-2, a higher percentage reported having been diagnosed with genital herpes in 1999-2004 compared with 1988-1994 (1.8% vs 0.4%, respectively; P<.001). These data show declines in HSV-2 seroprevalence, suggesting that the trajectory of increasing HSV-2 seroprevalence in the United States has been reversed. Seroprevalence of HSV-1 decreased but the incidence of genital herpes caused by HSV-1 may be increasing.
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              High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma.

              Human papillomavirus (HPV) DNA tumors actively integrating the E6 and E7 oncogenes have a distinct biologic behavior resulting in a more favorable prognosis. To which extent the viral integration by itself, and/or the associated wild-type (wt) TP53 status, and/or a functional p16 contribute to prognosis is unclear. To clarify how the presence of high-risk (HR) -HPV, TP53, and p16INK4a status interact with clinical outcome, we considered a retrospective series of 90 consecutive oropharyngeal cancer patients treated primarily with surgery. Seventeen (19%) patients showed integrated HPV 16 DNA (HPV positive), wt TP53 in all but two patients, normal p16INK4a in 15 assessable patients, and p16 expression in all 17 patients. Thirty-five patients (39%), two of whom were HPV positive, harbored TP53 mutations. p16INK4a deletion and p16 null immunophenotype occurred in 28 and 58 patients, respectively, and was similarly distributed in both patients with mutated TP53 (48% and 82%, respectively) and in patients with wt TP53 (46% and 77%, respectively). Statistical analysis showed that HPV-positive status significantly affects all investigated end points: overall survival (P = .0018), incidence of tumor relapse (P = .0371), and second tumor (P = .0152), whereas TP53 and p16INK4a status and p16 expression were not prognostic by themselves. Our molecular and clinical results are in agreement with previous findings but provide additional information into the biologic mechanisms involved in HR-HPV oropharyngeal cancer in comparison to HPV-negative tumors. According to the reduced risk of relapse and second tumors associated with HR-HPV positivity of oropharyngeal cancer, the therapeutic strategy and follow-up procedures should be reviewed.

                Author and article information

                Journal of Clinical Oncology
                American Society of Clinical Oncology (ASCO)
                November 10 2011
                November 10 2011
                : 29
                : 32
                : 4294-4301
                [1 ]Anil K. Chaturvedi, Eric A. Engels, Ruth M. Pfeiffer, Nicolas Wentzensen, William F. Anderson, and Philip S. Rosenberg, National Cancer Institute; Sean Altekruse, Surveillance, Epidemiology, and End Results Program, National Cancer Institute, Rockville, MD; Brenda Y. Hernandez and Marc T. Goodman, Cancer Research Center of Hawaii, Honolulu, HI; Weihong Xiao, Esther Kim, Bo Jiang, and Maura L. Gillison, The Ohio State University, Columbus, OH; Maria Sibug-Saber, Wendy Cozen, and Lihua Liu, University of...
                © 2011


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