Gary M. Clifford

Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review

Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear. We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site. Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site–specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx.

Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update

Data on human papillomavirus (HPV) type distribution in invasive and pre‐invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV‐based screening tests. A meta‐analyses of HPV type distribution in invasive cervical cancer (ICC) and high‐grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74–77%) than in Africa, Asia and South/Central America (65–70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under‐represented, and other high‐risk HPV types significantly over‐represented in HSIL compared to ICC, suggesting differences in type‐specific risks for progression. Data on HPV‐typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.

Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis

This study investigated regional variations in the contribution made by different human papilloma (HPV) types to invasive cervical cancer (ICC). A total of 85 studies using polymerase chain reaction to estimate HPV prevalence in ICC were identified. Data on HPV prevalence were extracted separately for squamous cell carcinoma (SCC) and for adeno- and adenosquamous-carcinoma (ADC). A total of 10 058 cases (8550 SCC, 1508 ADC) were included in pooled analyses. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16, 18, 45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70. In SCC, HPV16 was the predominant type (46–63%) followed by HPV18 (10–14%), 45 (2–8%), 31 (2–7%) and 33 (3–5%) in all regions except Asia, where HPV types 58 (6%) and 52 (4%) were more frequently identified. In ADC, HPV prevalence was significantly lower (76.4%) than in SCC (87.3%), and HPV18 was the predominant type in every region (37–41%), followed by 16 (26–36%) and 45 (5–7%). The overall detection of HPV DNA was similar in different regions (83–89%). A majority of ICC was associated with HPV16 or 18 in all regions, but approximately a quarter of all ICC cases were associated with one of 16 other HPV types, their distribution varying by region.

Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis.

We set out to estimate the age and genotype-specific prevalence of cervical human papillomavirus (HPV) DNA in women with normal cervical cytology worldwide by meta-analysis of a systematic literature review. Reports on HPV prevalence published between January, 1995, and January, 2005, were retrieved. To be included, studies required information on cervical cytology, plus detailed descriptions of study populations, methods used to collect cervical samples, and assays used for HPV DNA detection and typing. Final analyses included 78 studies that could be separated into women with normal cytology, and of which subsets of 44 and 48 studies had data on age and type-specific HPV prevalence, respectively. Overall HPV prevalence in 157 879 women with normal cervical cytology was estimated to be 10.4% (95% CI 10.2-10.7). Corresponding estimates by region were Africa 22.1% (20.9-23.4), Central America and Mexico 20.4% (19.3-21.4), northern America 11.3% (10.6-12.1), Europe 8.1% (7.8-8.4), and Asia 8.0% (7.5-8.4). In all world regions, HPV prevalence was highest in women younger than 35 years of age, decreasing in women of older age. In Africa, the Americas, and Europe, a clear second peak of HPV prevalence was observed in women aged 45 years or older. On the basis of these estimates, around 291 million women worldwide are carriers of HPV DNA, of whom 32% are infected with HPV16 or HPV18, or both. The HPV types most commonly detected are similar to those most commonly described in pre-neoplastic and cancer cases, although the relative contribution of HPV16 and HPV18 is substantially lower in cytologically normal women.

WORLDWIDE DISTRIBUTION OF HUMAN PAPILLOMAVIRUS TYPES IN CYTOLOGICALLY NORMAL WOMEN IN THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER HPV PREVALENCE SURVEYS: A POOLED ANALYSIS

BACKGROUND The proportion of women infected with human papillomavirus (HPV) varies greatly across populations, as might the distribution of HPV types. We aimed to compare HPV-type distribution in representative samples of women from different world regions. METHODS Women were randomly selected from the general population of 13 areas from 11 countries (Nigeria, India, Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy, and Spain). A standardised protocol was used for cervical specimen collection. All HPV testing was by GP5+/6+ PCR-based EIA. The proportion of HPV-positive women infected with different HPV types was compared by study area and between pooled regions with age-adjusted odds ratios (ORs) with corresponding 95% floating CIs. FINDINGS 15 613 women aged 15-74 years without cytological abnormalities were included in a pooled analysis. Age-standardised HPV prevalence varied nearly 20 times between populations, from 1.4% (95% CI 0.5-2.2) in Spain to 25.6% (22.4-28.8) in Nigeria. Although both overall HPV prevalence and HPV16 prevalence were highest in sub-Saharan Africa, HPV-positive women in Europe were significantly more likely to be infected with HPV16 than were those in sub-Saharan Africa (OR 2.64, p=0.0002), and were significantly less likely to be infected with high-risk HPV types other than HPV16 (OR 0.57, p=0.004) and/or low-risk HPV types (OR 0.44. p=0.0002). Women from South America had HPV-type distribution in between those from sub-Saharan Africa and Europe. Heterogeneity between areas of Asia was significant. INTERPRETATION Heterogeneity in HPV type distribution among women from different populations should be taken into account when developing screening tests for the virus and predicting the effect of vaccines on the incidence of infection.

Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis.

This meta‐analysis investigated human papillomavirus (HPV) prevalence in vulvar, vaginal and anal intraepithelial neoplasia (VIN, VAIN, AIN) grades 1–3 and carcinoma from 93 studies conducted in 4 continents and using PCR assays. Overall HPV prevalence was 67.8%, 85.3% and 40.4% among 90 VIN1, 1,061 VIN2/3 and 1,873 vulvar carcinomas; 100%, 90.1% and 69.9% among 107 VAIN1, 191 VAIN2/3 and 136 vaginal carcinomas; and 91.5%, 93.9% and 84.3% among 671 AIN1, 609 AIN2/3 and 955 anal carcinomas, respectively. HPV16 was found more frequently (>75%) and HPV18 less frequently (<10%) in HPV‐positive vulvar, vaginal and anal carcinomas than in cervical carcinoma. HPV6 and 11 were common in VIN1 and AIN1, but not in VAIN1. HPV prevalence in vulvar carcinoma varied most by histological type (69.4% in warty‐basaloid and 13.2% in keratinized type) and was also higher in women 60 years or younger and in studies carried out in North America. HPV prevalence in anal carcinoma was higher among women (90.8%) than men (74.9%), but no difference by gender emerged in North America. The majority of AIN2/3 derived from studies of HIV‐positive individuals and/or men who have sex with men. Among AIN2/3, HIV infection was associated with higher HPV prevalence, more multiple‐type infections and a relative under‐representation of HPV16. In conclusion, ∼40% of vulvar, 60% of vaginal and 80% of anal carcinoma may be avoided by prophylactic vaccines against HPV16/18. This proportion would be similar for the corresponding high‐grade lesions of the vagina and anus, but higher for VIN2/3 (75%) than for vulvar carcinoma.

Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication

Pooled data on human papillomavirus (HPV) type distribution in invasive cervical cancer (ICC) can help to predict the potential impact of HPV type‐specific vaccines and screening tests, and to understand the carcinogenicity of HPV types. We performed a meta‐analysis of HPV type‐specific prevalence data published from 1990 to 2010, including a total of 243 studies and 30,848 ICC. The proportion of ICC associated with HPV16 and/or 18 (HPV16/18) was between 70 and 76% in all world regions except Asia. In Western/Central Asia, 82% of ICC was HPV16/18‐associated compared to only 68% in Eastern Asia. The 12 most common HPV types identified, in order of decreasing prevalence, were HPV16 (57%), 18 (16%), 58, 33, 45, 31, 52, 35, 59, 39, 51 and 56. The prevalence of other types, phylogenetically related to those above, ranged from <0.1% for HPV85 to 0.6% for HPV68. Overall HPV prevalence increased significantly from 85.9% in studies published from 1990 to 1999 to 92.9% in studies published from 2006 to 2010. Prevalence increases were large for multiple infections (from 4.0 to 15.7%) and for HPV16 (from 51.8 to 60.0%, including HPV16 alone or in multiple infections). Smaller but significant increases in prevalence were also seen for HPV39, 53 and 58. A large amount of recently published data has improved the understanding of the contribution of a broad range of HPV types to ICC in different world regions. However, estimating the fraction of ICC attributable to different types is increasingly complicated by the detection of multiple HPV infections in ICC.

Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis

Particular types of human papillomavirus (HPV) infection may preferentially progress from high-grade squamous intraepithelial lesions (HSIL) to squamous cell carcinoma of the cervix (SCC). We performed a meta-analysis of published data to compare HPV type distribution in HSIL and SCC. HPV16, 18 and 45 were each more prevalent in SCC than HSIL, whereas the reverse was true for other oncogenic types including HPV31, 33, 52 and 58. These data suggest that HSILs infected with HPV16, 18 and 45 preferentially progress to SCC. This may have implications for follow-up protocols of future HPV-based cervical cancer screening programmes and for HPV vaccine trials.

Human Papillomavirus Genotype Distribution in Low-Grade Cervical Lesions: Comparison by Geographic Region and with Cervical Cancer

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.

Human papillomavirus types in 115,789 HPV‐positive women: A meta‐analysis from cervical infection to cancer

Genotyping may improve risk stratification of high‐risk (HR) human papillomavirus (HPV)‐positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta‐analysis of cross‐sectional HR HPV‐type distribution in 115,789 HPV‐positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low‐grade squamous intraepithelial lesions (LSIL) and 6,616 high‐grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR‐based studies worldwide. No strong differences in HPV‐type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20–28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios = 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios = 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV‐positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV‐based screening programs.