Human papillomavirus and rising oropharyngeal cancer incidence in the United States

Abstract

Purpose: 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.

Results: 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.

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

Fig 1.

Prevalence of human papillomavirus (HPV) infection in oropharyngeal cancers across four calendar periods (1984 to 1989, 1990 to 1994, 1995 to 1999, and 2000 to 2004) is shown for any HPV infection as determined by (A) the Inno-LiPA assay, (B) HPV16 viral load, (C) HPV16 E6/E7 oncogene expression, and (D) HPV16 in situ hybridization. Solid lines and circles represent observed prevalence estimates. Dotted lines and squares represent prevalence estimates corrected for potential loss in assay sensitivity because of the age of the specimens. The number of specimens evaluable for each assay is shown below the x-axis.

Fig 2.

Follow-up for overall survival began on the date of cancer diagnosis and ended at death or the last day of follow-up (November 1, 2009, for Hawaii; December 31, 2007, for Iowa; and May 31, 2010, for Los Angeles). Median follow-up among surviving patients was 112 months (120 for human papillomavirus–negative [HPV−] and 110 for HPV-positive [HPV+] patients). (A) Kaplan-Meier survival estimates and 95% CIs (shaded area) for patients with HPV+ (solid line) and HPV− (dashed line) oropharyngeal cancer, as determined by the Inno-LiPA assay. (B) Median Kaplan-Meier survival estimates in months (circles) and 95% bootstrap CIs (vertical lines) across four calendar periods for oropharyngeal cancers in 17 registries in the Surveillance, Epidemiology, and End Results (SEER) program and for the 271 tested oropharyngeal cancers, including survival for all oropharyngeal cancers, HPV+ oropharyngeal cancers, and HPV− oropharyngeal cancers. (*) Median survival has not yet been reached. Median survival of oropharyngeal cancers in SEER17 was 25 months during 1984 to 1989, 31.9 months during 1990 to 1994, 43.6 months during 1995 to 1999, and 64.1 months during 2000 to 2004. Median survival of tested patients who had oropharyngeal cancer was 24.1 months during 1984 to 1989, 24.4 months during 1990 to 1994, 56.7 months during 1995 to 1999, and was not yet reached during 2000 to 2004. Median survival of patients who had HPV+ oropharyngeal cancer was 43 months during 1984 to 1989, 37.6 months during 1990 to 1994, 142.2 months during 1995 to 1999, and was not yet reached during 2000 to 2004. Median survival of patients who had HPV− oropharyngeal cancer was 20.9 months during 1984 to 1989, 18.3 months during 1990 to 1994, 27.7 months during 1995 to 1999, and 20.2 months during 2000 to 2004.

Fig 3.

Incidence rates for overall oropharyngeal cancer, human papillomavirus (HPV)–positive oropharyngeal cancers, and HPV-negative oropharyngeal cancers during 1988 to 2004 in Hawaii, Iowa, and Los Angeles. Incidence rates for HPV-positive oropharyngeal cancers increased from 0.8 per 100,000 during 1988 to 1990 to 2.6 per 100,000 during 2003 to 2004. Incidence rates for HPV-negative oropharyngeal cancers significantly declined from 2.0 per 100,000 during 1988 to 2004 to 1.0 per 100,000 during 2003 to 2004. Overall incidence of oropharyngeal cancers increased from 2.8 per 100,000 during 1988 to 1990 to 3.6 per 100,000 during 2003 to 2004.

Fig 4.

(A) Observed and projected incidence rates and bootstrap 95% CIs (ages 30 to 84 years) for oropharyngeal cancers overall (solid squares), oropharyngeal cancers among men (solid circles), oropharyngeal cancers among women (open circles), and cervical cancers (open squares). (B) Projected annual number of patients (ages 30 to 84 years) of oropharyngeal cancers overall, oropharyngeal cancers among men, oropharyngeal cancers among women, and cervical cancers through the year 2030. (C) Observed and projected incidence rates for oropharyngeal (solid squares), oral cavity (open squares), larynx (solid circles), and other pharynx (open circles) cancers. (D) Projected annual number of patients with oropharyngeal, oral cavity, laryngeal, and other pharynx cancers through the year 2030. Observed incidence rates during 1973 to 2007 from nine registries within the Surveillance, Epidemiology, and End Results (SEER) program were used in age-period-cohort models to project expected incidence through the year 2030. Projected incidence rates were applied to the 2008 US population projections to calculate the annual number of patients. Oropharyngeal cancers included base of tongue (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3] topography code C019), lingual tonsil (C024), soft palate not otherwise specified (NOS; C051), uvula (C052), tonsil (C090-099), oropharynx (C100-109), and Waldeyer ring (C142). Oral cavity cancers included lip (C000-009), oral tongue (C020-23, C028, and C029), gum (C030-039), floor of mouth (C040-049), hard palate (C051, C058, and C059), and other and unspecified parts of the mouth (C060-069). Laryngeal cancers included glottis (C320), supraglottis (C321), subglottis (C322), laryngeal cartilage (C323), overlapping lesion of larynx (C328), and larynx NOS (C329). Other pharynx cancers included nasopharynx (C110-119), pyriform sinus (C129), postcricoid region (C130), hypopharynx (C130-139), and pharynx NOS (C140 and C148). Oropharyngeal cancers included both HPV-related and HPV-unrelated (soft palate NOS and uvula) anatomic subsites because projections were conducted for all head and neck cancer sites. Oropharyngeal, oral cavity, laryngeal, and other pharynx cancers were restricted to squamous cell histologies (ICD-O-3 codes 8050-8076, 8078, 8083, 8084, and 8094). Cervical cancers (C530-539) included all histologic subtypes.