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. 2003 Jan 28;88(1):63–73. doi: 10.1038/sj.bjc.6600688

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

G M Clifford 1,*, J S Smith 1, M Plummer 1, N Muñoz 1, S Franceschi 1
PMCID: PMC2376782  PMID: 12556961

Abstract

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.

Keywords: human papillomavirus, cervical carcinoma, squamous cell carcinoma, adenocarcinoma, epidemiology, literature review

Epidemiological studies have clearly established human papilloma-virus (HPV) infection as the central cause of invasive cervical cancer (ICC). This is the second most common cancer among women worldwide and the most common female cancer in large areas of the developing world where an estimated 80% of new cases arise (Parkin et al, 1999). Studies in 22 countries, coordinated by the International Agency for Research on Cancer (IARC), identified HPV DNA in almost all (99.7%) (of about 1000) cases of cervical cancer (Walboomers et al, 1999).

Approximately 40 distinct HPV types are known to infect the genital tract and epidemiological studies to date suggest that at least 14 of these, called oncogenic or high-risk (HR) types, are significantly associated with progression to ICC (Bosch et al, 1995). Most of these HR types are phylogenetically related to either HPV16 (31, 33, 35, 52 and 58) or HPV18 (39, 45, 59 and 68) (Chan et al, 1995). Limited evidence suggests that their distribution may vary by region (Bosch et al, 1995).

HPV vaccines hold great promise to reduce the global burden of ICC any potential vaccine be multivalent since prior infection with one type does not appear to decrease the risk of infection by another HPV type (Koutsky et al, 2002; Combita et al, 2002; Liaw et al, 2001). In this however, to collate all relevant published data to identify the most prevalent HPV types associated with ICC worldwide and within five geographic regions.

Materials and methods

Study selection

Source material was selected from citations listed in Medline and ISI Current Contents databases and from references cited in the selected papers. Key search terms included: cervical cancer, HPV, human, female, and polymerase chain reaction (PCR). The review was limited to studies that included a minimum of 20 ICC cases; carcinomas in situ were excluded. Studies had to provide a clear description of the use of PCR-based assays to identify HPV DNA. Studies using nonamplified hybridisation methods only were excluded based on the reduced sensitivity of such methods in comparison to PCR (Gravitt et al, 1991; Schiffman et al, 1991; Guerrero et al, 1992). Furthermore, articles were only included if type-specific prevalence of at least one HPV type other than HPV6, 11, 16 or 18 was reported. For articles where study methods suggested that additional type-specific data were available, these data were requested from the authors (Yang et al, 1997; Eluf-Neto et al, 1994; Chaouki et al, 1998; Meyer et al, 1998; Chen et al, 1999; Lin et al, 2001). If data or data subsets had been published in more than one article, only the publication with the largest sample size was included.

Data abstraction

For each study, the following key information was extracted: country of sample; sample size; mean age; study year; distribution of cases by histological type; type of cervical specimen (e.g., fresh/fixed biopsies or exfoliated cells) and PCR primers used to detect HPV positive samples; type-specific and overall prevalence of HPV infection. Where available, data on HPV-specific prevalence were extracted independently for squamous cell carcinoma (SCC) and for adeno- and adenosquamous carcinoma (henceforth collectively termed ADC). Where histology-specific HPV prevalence was not reported, cases were classified as being of ‘unspecified’ histology. Each study was classified into one of five geographical regions: Africa, Asia, Europe, North America and Australia, or South and Central America. For studies comparing HPV prevalence across regions (Munoz et al, 1992; Bosch et al, 1995; Sebbelov et al, 2000), data were separated into their regional components.

Studies included

Of studies published up to February 2002 on Medline identified by our search criteria, 82 qualified for inclusion (no additional studies were included from ISI Current Contents). Three studies were conference abstracts containing the detailed information required for inclusion (Illades-Aguiar et al, 2000; Nindl et al, 2001; Rabelo-Santos et al, 2001). In the course of contacting authors, additional data became available for two studies expanded since the original publication (Burger et al, 1996; Andersson et al, 2001). Detailed information on the design of each of the 85 included studies is listed in the appendix.

Estimation of type-specific prevalence

HPV prevalence data were expressed as percentages of all cases tested for HPV. Multiple infections (3.7% of all ICC cases) were separated into constituent types, thus type-specific prevalence represents that in either single or multiple infections. Cases with specimens considered to be inadequate for PCR testing were excluded. Type-specific prevalence is presented for the 18 most common HPV types as identified by this review (HPV types 6, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73 and 82 also known as MM4, W13B or IS39) in order of descending prevalence for each subgroup analysis. Consensus PCR primers My09/11 (Bernard et al, 1994), GP5+/6+ (Chaouki et al, 1998) and SPF10 (Kleter et al, 1999) were considered to amplify all 18 HPV types, L1C1/L1C2 (Nakagawa et al, 1996) to amplify all types, but HPV73 and 82, GP5/6 to amplify types 6, 11, 16, 18, 31, 33, 35 and 45 only (Roda Husman et al, 1995), and pU1M/2R (Harima et al, 2002) to amplify types 6, 16, 18, 31, 33, 35, 52, 56, 58 and 59 only. For other consensus and type-specific PCR primers, only those HPV types specified in the individual reports were considered amplifiable. For HPV-specific prevalence, only studies testing for a particular HPV type contribute to the analysis for that type, and therefore sample size varies between the type-specific analyses.

Statistical analyses

Sources of variation in overall HPV prevalence were investigated by unconditional multiple logistic regression analysis (Breslow and Day, 1980). The final model included the following sources of variation: geographical region, histological type of ICC, type of specimen for HPV DNA testing, and type of PCR primers used. Mean age and study year were found not to be significantly related to overall HPV prevalence. Adjustment of overall HPV prevalence for these variables was done using the adjust command in Stata version 7.0, based on probability estimates from the logistic regression model. Confidence intervals for overall HPV prevalence were calculated assuming the nonindependence of cases within the same study using the cluster option in Stata (White, 1980). P-values comparing the prevalence of particular HPV types in subsets of ICC cases refer to χ2 tests.

Results

Meta-analysis of overall HPV prevalence

A total of 10 058 ICC cases from the 85 identified studies were included in this meta-analysis of HPV prevalence (Table 1). A majority of cases came from studies performed in Asia (31%) and Europe (33%), with African studies representing the smallest proportion of cases (6%). HPV prevalence was reported stratified by histological type for 73% of the cases: 5825 SCC cases and 1508 ADC cases. In total, 12 studies included only SCC and seven studies included only ADC.

Table 1. Region- and histology-specific distribution of included studies and ICC cases.

        Number (%) of cases with histology-specific HPV data
Region No. of studies Countries represented No. of cases SCC ADC Unspecified
Africa 6 Algeria, Benin, Guinea, Mali, Morocco, Senegal, South Africa, Tanzania, Uganda 609 204 (33.5) 21 (3.4) 384 (63.1)
Asia 28 Mainland China, India, Indonesia, Japan, Korea, Malaysia, Philippines, Taiwan, Thailand 3091 2273 (73.5) 381 (12.3) 437 (14.1)
Europe 32 Austria, Czech Republic, Denmark, Finland, France, Germany, Greece, Greenland, Holland, Hungary, Ireland, Italy, Norway, Poland, Russia, Sweden, UK 3336 2010 (60.3) 603 (18.1) 723 (21.7)
North America and Australia 13 Australia, Canada, USA 1562 914 (58.5) 450 (28.8) 198 (12.7)
South and Central America 12 Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Honduras, Mexico, Panama, Paraguay, Peru 1460 424 (29.0) 53 (3.6) 983 (67.3)
Total 85   10 058 5825 (57.9) 1508 (15.0) 2725 (27.1)
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HPV=human papillomavirus; ICC=invasive cervical cancer; SCC=squamous cell carcinoma; ADC=adeno/adenosquamous carcinoma.

Adjusted overall HPV prevalence ranged from 79.3% in Asia to 88.1% in North America and Australia, but did not differ significantly between regions (Table 2). HPV DNA was significantly less likely to be detected in ADC (76.5%) than in SCC (87.3%) (P<0.001). DNA detection in ICC of unspecified histology (89.2%) was similar to that in SCC.

Table 2. Prevalence of HPV by region, histological type, HPV DNA specimen and PCR primers used.

Variable No. of studies No. of cases Crude HPV prevalence (%) Adjusteda HPV prevalence (%) 95% confidence intervals
Region
 Africa 6 609 88.8 86.5 (76.4–92.7)
 Asia 28 3091 83.1 79.3 (73.7–84.0)
 Europe 32 3336 85.9 86.7 (82.5–90.0)
 North America and Australia 13 1562 87.5 88.1 (83.6–91.5)
 South and Central America 12 1460 89.3 87.7 (83.1–91.2)
           
Histological type
 Squamous cell carcinoma 47 5825 86.9 87.3 (84.8–89.5)
 Adeno(squamous) carcinoma 45 1508 76.7 76.5 (72.3–80.3)
 Unspecified 48 2725 89.0 89.2 (85.1–92.3)
           
HPV DNA specimen
 Fixed biopsies 34 3324 84.3 83.3 (78.9–86.9)
 Fresh biopsies 27 3992 88.4 87.8 (84.9–90.2)
 Unspecified biopsies 8 496 87.1 87.2 (82.3–90.9)
 Cervical exfoliated cells 13 1444 80.1 78.9 (68.5–86.5)
 Cells and biopsies 3 802 93.5 92.5 (87.3–95.7)
           
Primers
 MY09/11 31 4355 85.9 83.3 (80.1–86.0)
 GP5/6 6 506 80.8 77.8 (64.9–87.0)
 GP5+/6+ 14 1681 92.2 90.1 (85.0–93.6)
 SPF10 3 275 96.7 97.2 (87.9–99.4)
 PU1M/2R 6 376 80.9 79.4 (68.8–87.0)
 L1C1/C2 5 655 91.2 88.0 (77.2–94.1)
 Combination 9 1351 88.4 86.4 (77.9–92.0)
 Other 4 166 84.3 89.3 (75.2–95.9)
TS-PCR only 7 693 73.6 74.7 (63.8–83.2)
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a

Adjusted for histological type, region, HPV DNA specimen and PCR primers.

Adjusted HPV prevalence was significantly higher from studies testing both cells and biopsies for HPV DNA (92.5%) than from studies testing either cervical exfoliated cells (78.9%) or fixed biopsies (83.3%) only. For PCR primers, highest HPV prevalence was obtained in studies using SPF10 primers (97.2%) and the lowest in studies using type-specific PCR (TS-PCR) only (74.7%). Adjusted overall HPV prevalence varied between 77.8 and 90.1% for other primer sets, but these differences were not statistically significant.

Meta-analysis of HPV type-specific prevalence

Owing to their similar overall and type-specific HPV prevalence, ICC of unspecified histology were combined with SCC for comparison of HPV type-specific prevalence by histological type (Figure 1). The most common HPV types identified 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. Other HPV types were detected in no more than 0.2% of ICC cases. There was considerable variation in HPV-specific prevalence between SCC and ADC. HPV16 was identified more often in SCC (55.2%) than in ADC (31.3%) (P<0.001). The same was found for the HPV16 phylogenetically related types 31, 33, 52 and 58 (P<0.001), but not 35. Conversely, HPV18 was more prevalent in ADC (37.7%) than in SCC (12.3%) (P<0.001). The HPV18 phylogenetically related type 45 was also more prevalent in ADC (5.8%) than in SCC (3.4%) (P=0.04).

Figure 1.

Figure 1

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Type-specific prevalence of HPV in 10 058 worldwide cases of invasive cervical cancer by histological type.

Comparison of HPV-specific prevalence in SCC by region is shown in Figure 2. In SCC, HPV16 was the predominant type in all regions studied, varying from 45.9% in Asia to 62.6% in North America and Australia. HPV18 was found consistently in 10–14% of SCC cases. In most regions, HPV45 (2–8%), 31 (2–7%) and 33 (3–5%) were the most prevalent types in SCC after types 16 and 18. In cases from Africa, the prevalence of HPV45 (8.0%) was more than twice that of either 31 (2.7%) or 33 (3.2%). In cases from Asia, HPV58 (5.8%) and 52 (4.4%) were found more commonly than HPV45, 31 and 33. Other HPV types varied considerably in their prevalence from region to region, but accounted for no more than 2% of ICC cases from any region.

Figure 2.

Figure 2

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Type-specific prevalence of HPV in 8550 cases of squamous cell and unspecified cervical carcinoma by region.

Sufficient ADC-specific data existed for the comparison of HPV-specific prevalence across Asia, Europe and North America and Australia (Figure 3). HPV18 was the predominant type (37.7%), found consistently in 37–41% of ADC cases in these regions, with HPV16 accounting for a smaller proportion (26–36%). HPV45 was the third most prevalent in each region, present in 5–7% of ADC cases vs only in 2–4% of SCC cases from these regions. The HPV16 phylogenetically related types 31, 33, 52 and 58 (but not 35) were all less prevalent in ADC cases than in SCC cases from each region.

Figure 3.

Figure 3

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Type-specific prevalence of HPV in 1508 cases of adeno- and adenosquamous cervical carcinoma by region.

Discussion

Two-thirds of ICC cases included in this meta-analysis were associated with HPV16 (51.0%) or 18 (16.2%) infection. However, more than 16 other HPV types were also associated with ICC, of which the most prevalent were types 45, 31, 33, 58 and 52 (collectively accounting for 18.3% of cases). The HPV16 family of viruses were more commonly found in SCC than ADC, whereas the HPV18 family were more common in ADC.

Geographical region

Overall detected HPV prevalence varied little between geographical regions (83–89%), but was low compared to the almost 100% HPV prevalence identified in studies using the most sensitive HPV detection methods (Walboomers et al, 1999). This reflects the fact that many studies used HPV DNA detection strategies of suboptimal sensitivity. When comparing prevalence by region and histology, we attempted to take account of alternative HPV DNA sources and PCR primers by adjustment. However, it is not known to what extent other unknown sources of variation such as sample storage conditions, specific PCR conditions and quality of histopathology may affect these comparisons. Residual differences in prevalence between regions could also be because of the yet unknown HPV types not amplified by the existing PCR primers.

There were many similarities in HPV type-specific distribution across the regions studied. In SCC, HPV16 was clearly the predominant type varying from 45.9% in Asia to 62.6% in Europe, with HPV18 being found consistently in 10–14% of the cases. Other rarer types appeared to vary in their distribution. In most regions, HPV45, 31 and 33 were the third, fourth and fifth most common genotypes, although not necessarily in that order. Asia appeared to be different with a larger proportion of cancers associated with HPV58 and 52, as highlighted by a recent study in China of 786 cases in which HPV58 and 52 were the third (10%) and fourth (9%) most common genotypes in ICC (Wong et al, 2000). Other types in SCC were too rare to make inferences on region-specific variations.

Histological type of ICC

This meta-analysis shows that overall HPV prevalence detected in ADC was significantly lower than that detected in SCC. This intriguing finding does not appear to be because of differences with respect to region or HPV detection methods as it persisted even after adjusting for these factors. ADC arises from tissue deeper in the interior of the cervix uteri than SCC, and it has been reported to be more difficult to appropriately sample exfoliated cells of ADC than SCC (Sasieni and Adams, 2001). However, most HPV detected in the present review was based on biopsy specimens (77%). A proportion of cervical ADC could be misclassified ADC arising from the endometrium or other rare histological variants of ADC, for example, clear cell and mesonephric, which have been suggested to be HPV-independent (O'Leary et al, 1998; Pirog et al, 2000).

Whereas HPV16 was the most common type in SCC followed by HPV18, the situation was reversed in ADC where HPV18 was the most common type, followed closely by HPV16. This difference has been described independently by many of the studies in this analysis and by studies outside the scope of this review (IARC, 1995). Compared to HPV16, HPV18 has been shown to be associated with increasing oncogenic potential in cell culture (Barbosa and Schlegel, 1989), as well as a more rapid transition to malignancy (Burger et al, 1996) and a poorer prognosis of cancer patients (Nakagawa et al, 1996; Hildesheim et al, 1999; Schwartz et al, 2001). Given the fact that columnar tissue giving rise to ADC is less accessible, and possibly less susceptible to HPV infections, than the squamous tissue of SCC, the establishment of ADC may require a relatively more aggressive infection. In addition to HPV16 and 18, this large meta-analysis facilitated the identification of differences for some rarer phylogenetically related types: the HPV16-related types 31, 33, 35, 52, and 58 were more prevalent in SCC (15.0% collectively) than in ADC (4.4% collectively); and HPV18-related 45 was more prevalent in ADC (5.8%) than SCC (4.2%). All these differences were seen consistently in all regions where the comparison was possible.

For all regions where histological comparison was possible, the ratio of ADC to SCC was higher than that reported by cancer registries (Parkin et al, 1997). For example, ADC represent 23.1% of histologically verified cases from Europe in this study, but only 15.3% of ICC cases reported to European cancer registries (Parkin et al, 1997). Since all seven studies of only ADC cases were from Europe, Japan or USA, ADC is over-represented in this meta-analysis, particularly in developed countries. No material differences in results were observed when SCC was compared with cancers of unspecified histology.

Study limitations

The different PCR primers employed by the studies covered in this analysis varied in their overall detection of HPV DNA, with the highest prevalence being obtained with SPF10 and GP5+/6+ primers, supporting findings from previous studies (Davies et al, 2001). Such variation is partly because of known differences in the range of HPV DNA types amplifiable by each primer set, and this was taken into consideration when estimating type-specific prevalence. However, there is also evidence that not all primer sets amplify individual HPV types with the same sensitivity (Qu et al, 1997; Kleter et al, 1999), and such differences are a potential source of bias in this analysis.

The type-specific prevalence reported for each individual type includes that in multiple infections, which were reported in a total of 3.7% of our ICC cases. Since many of the included studies tested for only a subset of HPV types, many multiple infections will have been missed. Hence, this meta-analysis was unable to estimate how often individual HPV types were found in the presence of other types, which limits the conclusions that can be made about individual HPV-type oncogenicity. In particular, a large proportion of cases positive for HPV6, which is not thought to be oncogenic, may be coinfected with an undetected HR HPV type.

The cases included in this meta-analysis are not representative of the worldwide distribution of ICC. The proportion of cases contributed by Africa (6.1%) and Asia (30.7%) in this study under-represent their proportional burdens of worldwide cervical cancer, which are 14.1 and 49.4%, respectively (Parkin et al, 1999). In contrast, the proportion of cases contributed by Europe (33.2%) and North America and Australia (15.5%) over-represent their proportional burdens, which are 15.7 and 4.4%, respectively. Adjustment of type-specific prevalence in all ICC cases (Figure 1) by weighting each region according to their cancer burden, however, did not materially effect the results, highlighting the general similarity of HPV-type distribution across regions (data not shown).

Furthermore, the cases in this meta-analysis were not drawn uniformly from across each region. Large areas have not been included (e.g., the Middle East and Indian subcontinent in Asia), while other specific populations such as Japan in Asia are over-represented. There is also evidence of inter-regional variation in HPV-type distribution; the high prevalence of HPV52 and 58 in Asia is more apparent in cases from China/Korea/Japan than in those from South East Asia. Hence, for the comparison of alternative regional groupings, HPV-specific prevalence is presented by study in the Appendix (Table A1).

Table AI. Study methods and prevalence of human papillomavirus by study and by region.

              HPV prevalence (% of all cases tested)
First author Reference Country HPV DNA source PCR primers used to identify all HPV +ve No. cases SCC (incl. unspec)/ADC Any 16 18 45 31 33 58 52 35 59 56 51 6 68 39 82 73 66 70
Africa
 Bosch FX JNCI (1995) Algeria, Benin, Guinea, Mali,Uganda,Tanzania Fresh biopsies My09/11 186 186/0 89.8 42.5 17.7 12.4 2.7 2.7 2.7 2.2 2.2 0.0 3.2 1.1 0.0 2.2   0.5   0.0  
 Bayo S Int J Epidemiol (2002) Mali Fresh biopsies GP5+/6+ 65 65/0 96.9 47.7 12.3 10.8 0.0 1.5 3.1 0.0 1.5 0.0 0.0 6.2 0.0 0.0 0.0   3.1 0.0  
 Chaouki N Int J Cancer (1998) Morocco Exfol. cells GP5+/6+ 186 173/13 94.6 67.7 12.4 4.8 3.8 2.7 0.0 1.1 0.5 1.6 0.5 0.0 0.5 0.0 0.0 0.0 0.0 0.5 0.0
 Lin P Cancer Epid Biomark Prev (2001) Senegal Exfol. cells MY09/11 +HMB01 51 51/0 64.7 37.3 7.8 9.8 0.0 5.9 2.0 3.9 2.0 0.0 2.0 0.0 2.0 0.0 0.0   0.0 0.0  
 Williamson AL J Med Virol (1994) South Africa Fresh biopsies MY09/11 68 60/8 80.9 45.6 1.5 1.5 5.9 5.9             0.0            
 ter Meulen J Int J Cancer (1992) Tanzania Exfol. cells GP 5/6 53 53/0 88.7 37.7 32.1 5.7 0.0 1.9                          
Region subtotal         609 588/21 88.8 50.2 14.1 7.9 2.6 3.1 1.6 1.6 1.4 0.6 1.6 1.2 0.4 0.8 0.0 0.3 0.7 0.2 0.0
                                                   
Asia
Huang S Int J Cancer (1997) China Fresh biopsies MY09/11 40 35/5 87.5 27.5 30.0 0.0 0.0 0.0 27.5 27.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0   0.0 0.0
Lin QQ Int J Cancer (1998) China Fresh/fixed biopsies MY09/11, GP5+/6+ 77 77/0 93.5 48.1 5.2 1.3 2.6 3.9 18.2 5.2 0.0 2.6 0.0 0.0 10.4 0.0 0.0 0.0 0.0 0.0 1.3
Lo KWK Gynecol Obstet Invest (2001) China Fresh biopsies MY09/11 121 107/14 78.5 48.8 11.6 0.0 0.8 5.0 6.6 0.8 0.0 0.0 0.8 0.0 0.0 0.0 0.0   0.0 0.0 0.0
Peng H Int J Cancer (1991) China Exfol. cells TS-PCR only 101 92/9 34.7 31.7       3.0                          
Stephen AL Int J Cancer (2000) China Fixed biopsies GP5+/6+ of TS-PCR neg samples only 34 24/10 88.2 61.8 8.8 2.9 0.0 2.9 2.9 0.0 0.0 2.9 0.0 0.0 0.0 0.0 0.0   0.0 0.0  
Munirajan AK Gynecol Oncol (1998) India Fresh biopsies pU-1M/pU-2R 43 43/0 69.8 53.5 9.3   0.0 2.3 2.3 0.0 2.3 0.0 0.0   0.0            
Bosch FX JNCI (1995) Indonesia, Philippines, Thailand Fresh biopsies My09/11 98 98/0 96.9 42.9 31.6 8.2 1.0 2.0 2.0 2.0 1.0 1.0 3.1 0.0 0.0 1.0   4.1   0.0  
Fujinaga Y J Gen Virol (1991) Japan Fresh biopsies pU-1M/pU-2R 39 39/0 84.6 48.7 12.8   5.1 5.1 7.7 2.6         0.0            
Harima Y Int J Radiat Oncol Biol Phys (2002) Japan Fresh biopsies pU-1M/pU-2R 84 79/5 76.2 26.2 4.8   2.4 2.4 7.1 2.4 0.0 0.0 0.0   1.2            
Kashiwabara K Acta Pathol Japan (1992) Japan Fixed biopsies L1C1/C2 93 68/25 58.1 48.4 6.5   0.0 1.1 0.0 3.2         0.0            
Maki H Jpn J Cancer Res (1991) Japan Biopsies L1 PCR 29 29/0 82.8 44.8 20.7     6.9 6.9 6.9         0.0            
Nagai Y Am J Clin Oncol (2001) Japan Exfol. cells L1C1/C2 293 239/54 85.3 25.3 3.1   3.8 4.1 3.1   1.7                    
Nakagawa S Cancer (1996) Japan Fresh biopsies L1C1/C2 +C2M 146 116/30 88.4 37.7 18.5 0.7 2.1 6.2 8.2 10.3 2.1 0.0 0.0 0.7 0.0 2.1 0.0     0.0 0.7
Nawa A Cancer (1995) Japan Fresh/fixed biopsies E6C1/C2 23 23/0 87.0 73.9 13.0     0.0                          
Saito J Gynecol Obstet Invest (2000) Japan Fixed biopsies pU-1M/pU-2R 66 66/0 75.8 34.8 12.1     10.6 1.5 6.1                      
Sasagawa T Cancer EpidBiomark Prev (2001) Japan Exfol. cells LCR-E7 84 72/12 89.3 42.9 14.3 1.2 6.0 1.2 3.6 10.7 1.2 0.0 0.0 4.8 1.2 0.0 0.0   0.0 0.0 0.0
Yamakawa Y Gynecol Oncol (1994) Japan Fixed biopsies TS-PCR only 64 0/64 67.2 32.8 39.1   1.6 0.0     7.8       0.0            
Hwang T J Korean Med Sci (1999) Korea Exfol. cells pU-1M/pU-2R 41 39/2 92.7 36.6 9.8   7.3 9.8 17.1 7.3 2.4                    
Kim KH Yonsei Med J (1995) Korea Fixed biopsies WD72/76 + WD66/67/154 30 30/0 70.0 53.3 16.7   0.0 0.0                          
Yadav M Med J Malaysia (1995) Malaysia Fresh biopsies MY09/11 23 23/0 95.7 73.9 65.2   13.0 4.3                          
Ngelangel C JNCI (1998) Philippines Fresh biopsies+exfol. cells GP5+/6+ 356 323/33 93.5 38.8 25.6 12.9 0.6 0.0 2.5 2.8 0.0 2.0 0.6 2.5 0.0 0.6 0.3 0.3 0.3 1.1 0.0
Chen SL Cancer (1993) Taiwan Fresh biopsies L1C1/C2, E6C1/C2/C3 43 40/3 72.1 46.5 4.7   0.0 2.3 2.3 2.3         0.0            
Chen TM Int J Cancer (1994) Taiwan Fresh biopsies MY09/11, pU-1M/pU-2R 433 382/51 79.0 46.2 12.2     6.5             0.0            
Lai HC Int J Cancer (1999) Taiwan Fresh biopsies MY09/11 94 87/7 86.2 47.9 8.5 0.0 2.1 4.3 18.1 2.1 0.0 0.0 0.0 0.0 0.0 1.1 0.0 0.0 0.0 0.0 0.0
Yang YC Gynecol Oncol (1997) Taiwan Fixed biopsies MY09/11 of TS-PCR neg samples only 136 120/16 83.1 63.2 6.6   0.7 5.1                          
Bhattarakosol P J Med Assoc Thai (1996) Thailand Fixed biopsies MY09/11 100 100/0 82.0 35.0 17.0     3.0             0.0            
Chichareon S JNCI (1998) Thailand Fresh biopsies+exfol. cells GP5+/6+ 377 338/39 94.7 54.4 20.7 1.6 1.9 1.3 2.7 2.4 0.5 1.6 0.0 0.0 0.5 0.0 0.5 0.0 0.0 0.0 0.5
Siritantikorn S Southeast Asian J Trop Med Public Health (1997) Thailand Lavage My09/11 23 21/2 60.9 56.5 4.3   4.3 4.3     0.0       0.0            
Region subtotal         3091 2710/381 83.1 43.4 15.3 4.5 2.0 3.4 5.4 4.2 1.0 1.1 0.4 1.0 0.5 0.5 0.2 0.4 0.1 0.3 0.3
                                                   
Europe
Birner P Mod Pathol (2001) Austria Fixed biopsies GP 5+/6+ 86 86/0 88.4 68.6 8.1 7.0 8.1 41.9 2.3 0.0 1.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.2 0.0 0.0
Baay MFD J Clin Microbiol (2001) Belgium Fixed biopsies GP5+/6+ of TS-PCR neg samples only 115 95/20 87.8 67.0 13.0 1.7 2.6 1.7 0.0 0.0 0.0 0.0 0.9 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.0
Tachezy R J Med Virol (1999) Czech Republic Fresh biopsies MY09/11 49 49/0 73.5 59.2 10.2 2.0 4.1 0.0 2.0 0.0 0.0 0.0 0.0 0.0   0.0 4.1 0.0 0.0 0.0 0.0
Hording U APMIS (1997) Denmark Fixed biopsies TS-PCR only 50 0/50 70.0 18.0 52.0     0.0                          
Sebbelov AM Microbes Infect (2000) Denmark Fixed biopsies GP5/6 of TS-PCR neg samples only 34 34/0 85.3 70.6 0.0 0.0 0.0 5.9     0.0                    
Iwasawa A Cancer (1996) Finland Fixed biopsies MY09/11 460 352/108 88.0 63.5 25.0     2.6                       0.0  
Lombard I J Clin Oncol (1998) France Fresh biopsies TS-PCR of SBH neg samples only 297 269/28 82.8 50.5 10.1 0.3 1.0 2.0 1.0 0.3 0.3       0.0   0.0        
Riou G Lancet (1990) France Biopsies TS-PCR of SBH neg samples only 106 89/17 84.0 54.7 16.0     5.7             0.0            
Milde-Langosch K Int J Cancer (1995) Germany Biopsies MY09/11 51 25/26 80.4 51.0 25.5   3.9 0.0     0.0       0.0            
Nindl I International Papillomavirus Conference Proceedings (2001) Germany Fixed biopsies My09/11 77 77/0 89.6 42.0 16.0   18.0 6.0 0.0 1.0 1.0     0.0 8.0   1.0     1.0  
Bosch FX JNCI (1995) Germany, Poland, Spain Fresh biopsies MY09/11 86 86/0 95.3 65.1 8.1 2.3 5.8 1.2 1.2 3.5 1.2 0.0 2.3 0.0 0.0 3.5 0.0 0.0   1.0  
Dokianakis DN Oncol Rep (1999) Greece Pap smears GP 5/6 77 75/2 58.4 2.6 36.4     3.9                          
Koffa M Int J Oncol (1994) Greece Fixed biopsies GP 5/6 39 32/7 76.9 35.9 38.5     10.3                          
Labropoulou V Sex Transmis Dis (1997) Greece Fresh biopsies MY09/11 35 35/0 97.1 54.3 22.9 0.0 5.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0   0.0  
Sebbelov AM Microbes Infect (2000) Greenland Fixed biopsies GP5/6 of TS-PCR neg samples only 32 32/0 84.4 81.3 0.0 0.0 3.1 3.1     0.0                    
Konya J J Med Virol (1995) Hungary Fresh biopsies L1C1/C2 +C2M 47 41/6 97.9 55.3 40.4   2.1 0.0 0.0 2.1         0.0            
O'Leary JJ J Clin Pathol (1998) Ireland Fixed biopsies GP5/6, GP1/2 20 20/0 90.0 80.0 10.0     0.0             0.0            
Sjyldberg BM Mod Pathol (1999) Ireland, Sweden Fixed biopsies GP 5+/6+ 38 0/38 60.5 23.7 26.3   0.0 0.0                          
Garzetti GG Cancer (1998) Italy Fresh biopsies GP 5/6 32 32/0 68.8 50.0 15.6   6.3 0.0     0.0       0.0            
Voglino G Pathologica (2000) Italy Fixed biopsies MY09/11, pU1M/2R 145 120/25 98.6 71.0 6.9   16.6 2.1     0.6                    
Karlsen F J Clin Microbiol (1996) Norway Fresh biopsies My09/11, GP5+6+, Oli1b/2I, CpI/II 361 361/0 98.3 68.4 14.1   1.1 8.3     0.6                    
Kleter B J Clin Microbiol (1999) Russia Fixed biopsies SPF10 180 129/51 100.0 64.4 9.4 7.8 3.9 1.1 1.7 1.1 1.7 0.0 2.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Munoz N Int J Cancer (1992) Spain Exfol. cells MY09/11 142 142/0 69.0 45.8 3.5   3.5 3.5     1.4       0.0   0.0     0.0  
Rodriguez JA Diag Mol Pathol (1998) Spain Fixed biopsies GP 5+/6+ 54 54/0 85.2 61.1 7.4 5.6 5.6 1.9 1.9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Andersson S Eur J Cancer (2001) Sweden Fixed biopsies My09/11 173 0/173 68.2 23.9 36.4 5.2 0.6 0.0 0.0 0.0 0.0 0.6 0.0 0.0 0.0   0.0        
Hagmar B Med Oncol Tumor Pharmacother (1992) Sweden Fixed biopsies MY09/11 71 71/0 74.6 38.0 9.9   16.9 8.5             0.0            
Wallin KL NEJM (1999) Sweden Fixed biopsies MY09/11, GP 5+/6+ 104 85/19 76.9 47.1 25.0 0.0 2.9 5.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0
Zehbe I J Pathol (1997) Sweden Fixed biopsies GP 5+/6+ 45 38/7 95.6 53.3 20.0 6.7 0.0 13.3 2.2 0.0 0.0   0.0 0.0 0.0            
Baay MFD Eur J Gynaec Oncol (1996) The Netherlands Fixed biopsies MY09/11, GP5/6, CpI/II 162 162/0 87.7 61.7 14.2 0.6 1.9 4.3 0.6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0   0.0 0.0
van den Brule AJC Int J Cancer (1991) The Netherlands Fresh biopsies GP5/6 + GP1/2 50 50/0 100.0 84.0 26.0   4.0 2.0             0.0            
Arends MJ Hum Pathol (1993) UK Fixed biopsies TS-PCR only 47 26/21 78.7 53.2 29.8     0.0             0.0            
Crook T Lancet (1992) UK Fresh biopsies TS-PCR of SBH neg samples only 28 23/5 89.3 71.4 17.9   0.0 0.0             0.0            
Giannudis A Int J Cancer (1999) UK Fixed biopsies GP 5+/6+ 43 43/0 100.0 81.4 9.3 2.3 0.0 4.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.3     0.0  
Region subtotal         3336 2733/603 85.9 56.0 17.5 2.9 4.2 4.4 0.8 0.5 0.5 0.1 0.6 0.0 0.3 0.4 0.3 0.0 0.3 0.1 0.0
                                                   
North America and Australia
Chen S Int J Gynecol Obstet (1999) Australia Fresh biopsies My09/11 186 153/33 91.9 53.8 17.2 4.8                              
Thompson CH Gynecol Oncol (1994) Australia Fresh/fixed biopsies pU-1M/pU-2R 103 103/0 86.4 65.0 18.4   2.9 0.0 0.0                        
Duggan MA Human Pathol (1995) Canada Fixed biopsies L1C1/C2 of DBH neg samples only 76 0/76 69.7 35.6 39.5   0.0 2.6     0.0       0.0           0.0
Bosch FX JNCI (1995) USA, Canada Fresh biopsies My09/11 57 57/0 93.0 57.9 15.8 14.0 5.3 0.0 0.0 0.0 0.0 0.0 3.5 0.0 0.0 1.8   0.0   0.0  
Burger RA JNCI (1996) USA Fresh biopsies My09/11 401 297/104 84.8 51.4 19.7 2.2 2.5 1.0 0.5 1.0 0.0 0.0 0.0 0.0 0.5 0.2 0.0 0.0 0.2 0.0 0.0
Burnett AF Gynecol Oncol (1992) USA Fixed biopsies My09/11 21 18/3 100.0 71.4 28.6   42.9 4.8     19.0       0.0            
Ferguson AW Mod Pathol (1998) USA Fixed biopsies MY09/11 27 0/27 59.3 25.9 25.9 7.4                              
Paquette RL Cancer (1993) USA Fresh biopsies MY09/11 45 28/17 93.3 48.9 40.0   4.4               0.0            
Schwartz SM J Clin Oncol (2001) USA Fixed biopsies MY09/11 465 354/111 88.2 58.5 23.2 1.3 2.4 3.4 0.0 0.0 0.2 0.0 0.0 0.0 2.4 0.0 0.2 0.0 0.2 0.2 0.0
Sebbelov AM Microbes Infect (2000) USA Fixed biopsies GP5/6 of TS-PCR neg samples only 53 53/0 98.1 77.4 3.8 0.0 20.8 30.2     0.0                    
Wistuba II Cancer Res (1997) USA Fixed biopsies SPF10 20 20/0 90.0 60.0 20.0   5.0 5.0                          
Resnick RM JNCI (1990) USA (+Holland) Fixed biopsies My09/11, WD72/76 33 29/4 100.0 75.8 15.2 3.0 3.0 3.0             0.0            
Pirog EC Am J Pathol (2000) USA (+Poland) Fixed biopsies SPF10 76 0/75 89.5 39.5 38.2 10.5 1.3 1.3 0.0 2.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0     0.0  
Region subtotal         1562 1112/450 87.5 54.9 22.1 3.3 3.9 3.2 0.2 0.6 0.4 0.0 0.2 0.0 1.1 0.2 0.1 0.0 0.2 0.1 0.0
                                                   
South and Central America
Bosch FX JNCI (1995) Argentina,Bolivia,Brazil,Chile,Colombia,Cuba,Panama,Paraguay Fresh biopsies MY09/11 505 505/0 92.9 50.5 9.5 7.3 6.9 3.6 2.2 3.2 2.0 2.8 0.6 1.0 0.2 0.4   0.2      
Alonio LV MEDICINA (2000) Argentina Biopsies GP 5+/6+ 30 30/0 93.3 46.7 20.0   3.3 3.3             6.7            
Eluf-Neto J Br J Cancer (1994) Brazil Exfol. cells GP 5/6 186 186/0 84.4 53.8 9.7   2.2 3.2             0.0            
Lorenzato F Int J Gynecol Cancer (2000) Brazil Exfol. cells MY09/11 59 59/0 89.8 59.3 38.5 0.0 11.9 5.1 3.4 1.7 3.4       0.0            
Rabelo-Santos SH International Papillomavirus Conference Proceedings (2000) Brazil Fixed biopsies GP 5+/6+ 56 51/5 80.4 57.1 5.4   1.8 8.9 0.0 0.0   0.0   0.0 0.0            
Munoz N Int J Cancer (1992) Colombia Exfol. cells MY09/11 87 87/0 72.4 50.6 5.7   5.7 0.0     3.4       0.0            
Herrero R JNCI (2000) Costa Rica Exfol. cells MY09/11 +HMB01 34 34/0 88.0 47.0 15.0 0.0 5.9 8.8 12.0 0.0 2.9 2.9 2.9 2.9 2.9 5.9 0.0   0.0 2.9 0.0
Ferrera A Int J Cancer (1999) Honduras Exfol. cells MY09/11 104 99/5 80.6 47.1 13.5 5.8 3.8 9.6 6.7 1.0 0.0 1.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0
Torroella-Kouri M Gynecol Oncol (1998) Mexico Fresh biopsies+Exfol. Cells MY09/11 +HMB01 69 59/10 87.0 42.0 14.5 10.1 2.9 0.0 4.3 2.9 0.0 4.3 1.4 0.0 0.0 1.4 4.3 1.4 0.0 1.4 1.4
Meyer T J Infect Dis (1998) Mexico Fresh biopsies MY09/11 60 60/0 96.7 43.3 16.7 3.3 23.3 6.7 0.0 1.7 1.7 0.0 1.7 0.0 3.3 0.0 1.7 3.3 0.0 0.0 0.0
Illades-Aguiar B International Papillomavirus Conference Proceedings (2001) Mexico Fresh biopsies MY09/11 74 66/8 97.3 60.8 10.8 0.0 10.8 1.4 4.1 2.7 0.0 0.0 0.0 0.0 1.4 0.0 0.0 0.0 0.0 0.0  
Santos C Br J Cancer (2001) Peru Fresh biopsies GP5+/6+ 196 171/25 94.9 56.1 12.2 4.6 9.7 4.1 2.0 7.7 3.6 0.5 1.0 1.0 0.0 0.0 2.6 0.0 0.0 1.0 0.5
Lo KWK Int J Cancer (2002) China Fresh biopsies MY09/11, GP5+/6+ 809 731/78 83.7 66.9 6.3 0.4 0.6 1.5 3.2 2.2                      
Mortazavi SH Asian Pacific J Cancer Prev (2002) Iran Fixed biopsies TS-PCR only 69 61/8 85.5 73.9 11.6     1.2                          
                                                   
Ishikawa H Cancer (2001) Japan Fixed biopsies TS-PCR only 52 52/0 76.9 53.8 23.1     1.9                          
Dybikowska A Oncol Rep (2002) Poland Exfol. cells MY09/11 53 53/0 53.8 48.1 0.0   1.9 1.9 1.9           0.0            
Pegoraro RJ Int J Gynecol Cancer (2002) South Africa Fresh biopsies MY09/11 190 190/0 98.4 46.8 14.2 4.7   10 1.1 1.6 1.6     0.0 0.5            
Cuzick J Br J Cancer (2000) UK Exfol. cells MY09/11 116 85/31 94 65.5 11.2 0.0 11.2 6.9 1.7 0.0 1.7 0.0 1.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Region subtotal         1460 1407/53 89.3 51.7 10.6 5.5 7.0 4.0 2.9 3.3 2.0 1.9 0.7 0.7 0.5 0.5 1.7 0.4 0.0 0.4 0.4
                                                   
Total       10 058 8550/2725 86.0 51.0 16.3 4.4 3.9 3.8 2.7 2.3 0.9 0.8 0.6 0.5 0.6 0.5 0.4 0.2 0.2 0.2 0.2  
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Given that HPV is considered a virtually necessary cause of ICC, we further examined results restricted to HPV DNA-positive cases. This increased type-specific prevalence by a factor of ≈1.1 consistently for each HPV type, with no impact on the relative distribution of HPV types. However, given that many of the PCR systems used by the included studies amplify only a subset of HPV types, many HPV-‘negative’ cases may actually be infected with other, unascertained, HPV types. Thus, we did not consider it appropriate to restrict to HPV-positive cases when comparing type-specific prevalence across studies where PCR methodology differed considerably.

However, in order to make a broad overall estimate if one does assume that, HPV DNA should be detectable in 100% of ICC and that the distribution of undetected types in HPV-negative cases is similar to that in positive cases, this meta-analysis suggests that vaccinating against HPV16 and 18 should prevent over 70% of worldwide ICC. However, a worldwide vaccine against only HPV16/18 may prevent a larger proportion of ICC in Europe, North America and Australia (≈75%), than in Africa, Central and South America and Asia (59–64%), where a larger proportion of ICC cases were associated with other HPV types. Although this study identifies at least 18 HPV types associated with ICC from around the world, the most important type after HPV16 and 18 appears to be HPV45, followed by types 31, 33, 58 and 52, the relative importances of which vary by region.

Acknowledgments

The work reported in this paper was undertaken by Dr Gary Clifford during the tenure of an IARC Postdoctoral Fellowship from the International Agency for Research on Cancer. We thank the Vaccine Development team (VAD) of the Department of Vaccines and Biologicals of the World Health Organization, Geneva and Swiss Bridge (Award 2001) who supported and contributed to the funding of this work. We are grateful to Dr Teresa Aguado, Coordinator, VAD and Dr Sonia Pagliusi, Scientist, VAD for their critical comments during the preparation of the manuscript, as well as to Dr Rolando Herrero. We also thank those authors who made additional data available from their published studies.

Appendix A

A comparison of alternative regional groupings, HPV prevalence is presented by the study in Table AI

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