Short Communication
Comparison of HPV type distribution in high-grade cervical lesions
and cervical cancer: a meta-analysis
GM Clifford1,*, JS Smith1, T Aguado2 and S Franceschi1
1Unit of Field and Intervention Studies, International Agency for Research on Cancer, 150, cours Albert Thomas, 69008, Lyon, France; 2Department of
Vaccines and Biologicals, WHO, Geneva, Switzerland
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.
British Journal of Cancer (2003) 89, 101–105. doi:10.1038/sj.bjc.6601024 www.bjcancer.com
& 2003 Cancer Research UK
Keywords: Human papillomavirus; high grade intraepithelial lesions; cervical cancer; squamous cell carcinoma; epidemiology;
meta-analysis
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Epidemiological studies have established human papillomavirus
(HPV) infection as the central cause of invasive cervical cancer
(ICC) and its precursor lesions (Walboomers et al, 1999).
However, only a fraction of precancerous lesions progress to
ICC. A strong candidate factor for differential progression is HPV
type (Lorincz et al, 1992).
Identifying HPV types that preferentially progress from high-
grade squamous intraepithelial lesions (HSIL) to ICC has
implications not only for follow-up protocols in ICC screening
programmes, but also for prophylactic type-specific HPV vaccine
trials. For ethical reasons, final outcome measures in such trials
will be the prevention of HSIL. However, it is important to know
whether the HPV type distribution in HSIL is representative of
those that go on to cause cancer.
Articles presenting HPV type-specific prevalence data were
identified from Medline. Studies had to include at least 20 cases
of squamous cell or histologically unspecified cervical cancer
(Clifford et al, 2002) and/or 20 histologically verified cases of HSIL.
In this study, HSIL refers both to lesions classified by the Bethesda
system, that is, CIN2/3, and those classified separately as CIN2 and
CIN3. Studies had to use polymerase chain reaction (PCR)-based
assays to identify HPV, and to present prevalence of at least one
type other than HPV6, 11, 16 or 18 (Clifford et al, 2002).
This report includes 8594 squamous cell carcinoma of the
cervix (SCC) cases (including 2725 of unspecified histology), as
previously reported in Clifford et al (2002), and 4338 HSIL cases
(1733 reported as CIN2/3, 1824 as CIN3, 729 as CIN2 and 52
as cervical carcinoma in situ)(detailed information on the HSIL
studies is reported in the Appendix). Compared to SCC, cases of
HSIL were more likely to be from (i) Europe and South/Central
America rather than other regions, (ii) studies that detected HPV
from exfoliated cells rather than biopsy specimens and (iii) studies
that used ‘broad’-spectrum (MY09/11, GP5þ /6þ and SPF10)
rather than other PCR primers (Table 1).
Type-specific prevalence is presented for the 14 most common
high-risk (HR) types identified in SCC (Table 2). As not all studies
tested for all 14 types, sample size varies between type-specific
analyses. Type-specific prevalence is expressed as a percentage of
all cases tested for HPV, and thus represents the prevalence in
either single or multiple infections.
Overall, HPV prevalence was slightly higher in SCC cases
(87.6%) than HSIL (84.2%) (SCC : HSIL ratio 1.04, 95% CI 1.03–
1.06) (Table 2). HPV16 was the most common type in both SCC
(54.3%) and HSIL (45.0%), but was more prevalent in SCC (ratio
of 1.21, 95% CI 1.16–1.26). HPV18 was also more prevalent in
SCC (12.6%) than in HSIL (7.0%), with a ratio of 1.79 (95% CI
1.56– 2.10). HPV45 was associated with a ratio of 1.85 (95% CI
1.35– 2.91), similar to that of HPV18. All other HR types included
in the analysis had ratios between 0.1 and 0.6 (Table 2).
The SCC : HSIL ratios for the eight most common HPV types
were additionally calculated within more homogeneous study
subgroups: (i) studies that did not report any multiple infections
(6558 SCC, 2182 HSIL), (ii) studies testing for HPV from biopsies
(7128 SCC, 1483 HSIL) and (iii) studies using ‘broad’-spectrum
PCR primers (5318 SCC, 3502 HSIL). The SCC : HSIL ratios were
also calculated separately for HSILs classified by the Bethesda
system and for CIN3 only. Across all these subanalyses, SCC :
HSIL ratios remained consistent for HPV16 (range: 1.04– 1.25),
HPV18 (1.46 –1.93) and HPV45 (1.20–4.61). HPV31, 33, 35, 52 and
58 were consistently associated with ratios of 0.3– 0.9, with the
exception of HPV58 for biopsy studies (1.06, 95% CI 0.73– 2.08).
Where sample size permitted, subanalyses were also stratified
by region. When estimated from studies within Asia, Europe
and South/Central America, respectively, there was no material
difference in SCC : HSIL ratios for HPV16 (1.46, 1.17, 1.40), HPV18
(1.74, 2.02, 1.46), HPV45 (4.35, 1.39, 1.20), HPV33 (0.56, 0.62, 0.76),
Received 29 November 2002; revised 14 March 2003; accepted 26
March 2003
*Correspondence: Dr GM Clifford; E-mail: clifford@iarc.fr
British Journal of Cancer (2003) 89, 101 – 105
& 2003 Cancer Research UK All rights reserved 0007 – 0920/03 $25.00
www.bjcancer.com
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HPV52 (0.39, 0.26, 0.64) or HPV58 (0.55, 0.24, 0.30). However,
notably high ratios were observed for HPV31 in South/Central
America (1.13, 95% CI 0.84–1.70) in comparison to Europe (0.41,
95% CI 0.36–0.48) and Asia (0.43, 95% CI 0.31–0.68), and for
HPV58 in China (including Taiwan and Hong Kong) (1.27, 95% CI
0.85– 2.51) in comparison to non-Chinese Asian countries
(0.37, 95% CI 0.27–0.58), raising the possibility of localised
variation in the malignant potential of particular HPV types (Chan
et al, 2002).
Our findings suggest that worldwide, HSIL infected with HPV16,
18 or 45 are more likely to progress to SCC than HSIL infected with
other HR types. This could be interpreted in two ways: either these
types have a greater potential to induce fully malignant
transformation, and/or these infections somehow preferentially
evade the host immune system. Compared to other HPV types,
HPV18 has been associated with increased oncogenic potential
in cell culture, screening failures and poorer cancer prognosis
(Hildesheim et al, 1999; Schwartz et al, 2001; Woodman et al,
2003). Thus, HPV18 enrichment in SCC may reflect its greater
oncogenic potential. Given its genetic similarity to HPV18, this
may also be true for HPV45. Conversely, compared to other HPV
types, HPV16 infections are more likely to persist and progress to
HSIL (Molano et al, in press). Both persistence of infection and
progression to HSIL have been shown associated with HPV16
variants (Londesborough et al, 1996). Thus, HPV16 enrichment in
SCC may be related to its greater ability to escape immune
surveillance compared to other types.
Even in countries with established screening programmes,
women still die from rapidly progressing cancers that escape
periodic examination. Given that HPV16, 18 and 45 appear to have
greater progressive potential, and in the event that future cervical
screening programmes include HPV typing, women infected with
HPV16, 18 and 45 may require closer surveillance than women
infected with other HR HPV types.
The demonstration that the HPV type distribution in HSIL is not
entirely representative of those that go on to cause cancer also has
important implications for prophylactic type-specific HPV vaccine
evaluation. This is because any beneficial effect identified by
randomised trials from the proportion of HSIL preventable by
HPV16 or HPV16/18 vaccines may be an underestimate of the
beneficial effect on the prevention of ICC.
ACKNOWLEDGEMENTS
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
Dr Massimo Tommasino for his critical comments during the
preparation of the manuscript.
Table 1 Distribution of SCC and HSIL cases by region and study characteristics
Lesion
No. of
studies
No. of
cases
Source region
(% of cases)
Cervical specimen for
HPV testing (% of cases)
PCR primers used
(% of cases)
SCC 78 8594 Africa (6.9), Asia (31.7), Broad spectruma (61.9)
Europe (32.0), North America/Australia Biopsies (83.4) Narrow spectrumb (15.5)
(13.0), South/Central America (16.5) Exfoliated cells (16.6) Combination/other (16.3)
Type-specific only (6.4)
Broad spectruma (80.8)
HSIL 53 4338 Africa (1.8), Asia (16.7), Europe Biopsies (34.1) Narrow spectrumb (7.9)
(52.4), North America (10.3), Exfoliated cells (65.9) Combination/other (7.4)
South/Central America (18.8) Type-specific only (3.9)
HPV¼ human papillomavirus; SCC¼ squamous cell/unspecified carcinoma of the cervix; HSIL¼ high-grade squamous intraepithelial lesion; PCR¼ polymerase chain reaction;
a‘Broad’-spectrum PCR primers include MY09/11, GP5+/6+ and SPF10. b‘Narrow’-spectrum PCR primers include GP5/6, L1C1/C2 and PU1M/2R.
Table 2 Comparison of overall and type-specific HPV prevalence between SCC and HSIL cases
SCC HSIL SCC : HSIL
HPV type n HPV (%) n HPV (%) prevalence ratioa
All 8550 87.6 4338 84.2 1.04 (1.03, 1.06)
16 8594 54.3 4338 45.0 1.21 (1.16, 1.26)
18 8502 12.6 4338 7.1 1.79 (1.56, 2.10)
33 8449 4.3 4302 7.2 0.59 (0.53, 0.68)
45 5174 4.2 2214 2.3 1.85 (1.35, 2.91)
31 7204 4.2 4036 8.8 0.48 (0.43, 0.54)
58 5646 3.0 2175 6.9 0.43 (0.37, 0.52)
52 5304 2.5 2153 5.2 0.48 (0.40, 0.60)
35 6223 1.0 2690 4.4 0.22 (0.18, 0.27)
59 4488 0.8 1636 1.5 0.55 (0.38, 0.97)
56 4493 0.7 2110 3.0 0.23 (0.18, 0.31)
51 4580 0.6 2171 2.9 0.20 (0.16, 0.27)
68 4148 0.5 1763 1.0 0.50 (0.33, 1.04)
39 3899 0.4 1841 1.1 0.35 (0.24, 0.66)
66 4799 0.2 1778 2.1 0.10 (0.08, 0.15)
HPV¼ human papillomavirus; SCC¼ squamous cell/unspecified carcinoma of the cervix; HSIL¼ high-grade squamous
intraepithelial lesion. aWith 95% confidence intervals.
Comparison of HPV type distribution in HSIL and SCC
GM Clifford et al
102
British Journal of Cancer (2003) 89(1), 101 – 105 & 2003 Cancer Research UK
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Appendix
Study methods and type-specific prevalence of human papilloma-
virus by study and by region are summarised in Table A1.
Comparison of HPV type distribution in HSIL and SCC
GM Clifford et al
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Table A1
HPV
DNA
PCR primers
used to
identify No.
CINII/
CINIII/
HPV-specific prevalence (% of all cases tested)
First author Reference Country source all HPV +ve cases CIS/HSIL Any 16 18 45 31 33 58 52 35 59 56 51 68 39 66
Africa
La Ruche Int J Cancer (1998) Ivory Coast Exfol. cells MY09/11 49 0/0/0/49 77.6 30.6 10.2 0.0 6.1 8.2 8.2 4.1 0.0 0.0 4.1 0.0 2.0 0.0
de Vuyst Sex Transm Dis (2003) Kenya Exfol. cells SPF10 29 0/0/0/29 96.6 34.5 3.4 6.9 6.9 3.4 6.9 24.1 17.2 0.0 3.4 10.3 6.9 0.0 10.3
Africa sub-total 78 0/0/0/78 84.6 32.1 7.7 2.6 6.4 6.4 7.7 11.5 6.4 0.0 3.8 3.8 3.8 0.0 10.3
Asia
Chan MKM Gynecol Oncol (1996) China Exfol. cells MY09/11 45 10/35/0/0 55.6 24.4 8.9 0.0 4.4
Chan PKS J Med Virol (1999) China Exfol. cells MY09/11 89 29/60/0/0 58.4 25.8 4.5 0.0 3.4 6.7 11.2 1.1 0.0 0.0 0.0 0.0 0.0 1.1 0.0
Wu CH Sex Transm Dis (1994) China Fixed
biopsies
TS-PCR only 34 13/15/6/0 76.5 35.3 20.6 0.0 5.9
Nagai Y Gynecol Oncol (2000) Japan Exfol. cells L1C1/L1C2 58 0/58/0/0 96.6 37.9 3.4 8.6 15.5 6.9 1.7
Saito J Jpn J Obstet Gynecol Pract (2001) Japan Exfol. cells L1C1/L1C2 38 0/0/0/38 100.0 34.2 18.4 0.0 7.9 7.9 13.2 34.2 0.0 15.8 0.0 13.2 2.6 0.0 2.6
Sasagawa T Cancer Epidemiol Biomarkers
Prev (2001)
Japan Exfol. cells LCR-E7 137 0/0/0/137 91.2 35.8 2.2 2.2 9.5 2.2 13.1 10.9 2.9 0.0 5.8 7.3 0.0 0.0 0.7
Yoshikawa H Jpn J Cancer Res (1991) Japan Biopsies L1C1/L1C2 31 0/0/20/11 90.3 38.7 9.7 6.5 12.9 3.2 12.9
Oh YL Cytopathology (2001) Korea Exfol. cells pU-1M/pU-2R 42 0/0/0/42 73.8 40.5 7.1 7.1 19.0
Lai HC Int J Cancer (2003) Taiwan Exfol. cells MY09/11 141 0/0/0/141 63.8 25.5 1.4 4.3 9.9 11.3
Ekalaksananan T J Obstet Gynaecol. Res (2001) Thailand Exfol. cells E1 primers 40 10/4/26/0 65.0 7.5 15.0 2.5
Lertworapreecha M Southeast Asian J Trop. Med
Public Health (1998)
Thailand Fixed
biopsies
MY09/11 50 0/50/0/0 74.0 36.0 12.0 8.0
Limbaiboon T Southeast Asian J Trop.
Med Public Health (2000)
Thailand Fixed
biopsies
MY09/11 21 0/21/0/0 100.0 33.3 14.3 4.8
Asia sub-total 726 62/243/52/369 76.4 31.4 6.9 1.0 4.9 6.7 10.5 11.2 1.6 2.3 3.0 4.0 0.4 0.5 0.7
Europe
Baay MFD Eur J Gynaecol. Oncol (2001) Belgium Fixed
biopsies
GP5+/6+ 97 42/55/0/0 82.5 56.7 6.2 0.0 0.0 6.2 6.2 2.1 2.1 0.0 2.1 1.0 1.0 0.0 1.0
Tachezy R Hum. Genet. (1999) Czech Republic Exfol. cells MY09/11 88 0/0/0/88 58.0 43.2 5.7 3.4 1.1 6.8 0.0 1.1 0.0 0.0 0.0 1.1 0.0 1.1 0.0
Sebbelov Res Virol. (1994) Denmark Fixed
biopsies
GP5/6 34 0/34/0/0 91.2 85.3 0.0 0.0 29.4
Bergeron B Am J Surg Pathol (1992) France Fresh
biopsies
L1 primers 53 0/0/0/53 92.5 56.6 3.8 1.9
Merkelbach-Bruse S Diagn Mol. Pathol (1999) Germany Fixed
biopsies
GP5/6 88 21/67/0/0 78.4 61.4 1.1 3.4 1.1
Meyer T Int J Gynecol Cancer (2001) Germany Fresh
biopsies
MY09/11 288 0/0/0/288 94.4 46.2 6.6 1.4 13.2 9.4 1.7 5.6 3.1 0.7 1.4 1.0 0.3 1.4 2.1
Nindl I J Clin Pathol (1999) Germany Exfol. cells GP5+/6+ 65 31/34/0/0 87.7 56.9 6.2 1.5 18.5 7.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.5
Nindl I Int J Gynecol Pathol (1997) Germany Exfol. Cells GP5+/6+ 85 0/0/0/85 83.5 36.5 2.4 5.9 12.9
Labropoulou V Sex Transm Dis (1997) Greece Fresh
biopsies
MY09/11 50 0/0/0/50 88.0 36.0 12.0 6.0 6.0 4.0 0.0
Paraskevaidis E Gynecol Oncol (2001) Greece Exfol. cells MY09/11 28 0/0/0/28 89.3 35.7 7.1 3.6 25.0 14.3 0.0 0.0 0.0 0.0 0.0 0.0
Sebbelov Res Virol. (1994) Greenland Fixed
biopsies
GP5/6 30 0/30/0/0 63.3 70.0 3.3 6.7 10.0
Butler D J Pathol (2000) Ireland Fixed
biopsies
TS-PCR only 27 0/27/0/0 85.2 70.4 3.7 3.7 3.7 0.0 0.0
O’Leary JJ Hum. Pathol (1998) Ireland Fixed
biopsies
GP5/6 20 0/20/0/0 95.0 95.0 0.0 0.0
Laconi Pathologica (2000) Italy Fixed
biopsies
GP5+/6+ 36 19/17/0/0 100.0 50.0 8.3 2.8 2.8 5.6 5.6 2.8 0.0 0.0
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MolecularandCellularPathology
Zerbini M J Clin Pathol (2001) Italy Exfol. cells MY09/11 89 0/0/0/89 79.8 50.6 3.4 2.2 7.9 9.0
Medeiros R Proceedings of International
Meeting of Gynaecological
Oncology (1997)
Portugal Fixed
biopsies
MY09/11 78 10/68/0/0 85.9 82.1 0.0 1.3
Bosch Cancer Epidemiol
Biomarkers Prev (1993)
Spain Exfol. cells MY09/11 157 0/157/0/0 70.7 49.0 0.6 1.3 5.7 0.6
Kalantari M Hum. Pathol (1997) Sweden Exfol. cells MY09/11 164 69/95/0/0 82.9 36.0 7.3 7.3 10.4
Zehbe I Virchows Arch (1996) Sweden Fixed
biopsies
GP5+/6+ 103 55/48/0/0 95.1 50.5 9.7 1.9 7.8 9.7 1.9 0.0 7.8 1.9 0.0
Bollen LJM Am J Obstet Gynecol (1997) The Netherlands Exfol. cells CpI/CPIIG 91 24/64/0/3 97.8 36.3 4.4 4.4 18.7 5.5 7.7 2.2 4.4 1.1 4.4 3.3
Cornelissen MTE Virchows Arch B Cell
Pathol Incl. Mol. Pathol (1992)
The Netherlands Fixed
biopsies
MY09/11 89 16/73/0/0 88.8 52.8 6.7 12.4 5.6
Reesink-Peters N Eur J Obstet Gynecol
Reprod Biol (2001)
The Netherlands Exfol. cells SPF10 216 44/172/0/0 97.7 56.9 13.9 19.4 11.6 8.3
Arends MJ Hum. Pathol (1993) UK Fixed
biopsies
TS-PCR only 40 20/20/0/0 60.0 50.0 10.0 0.0
Cuzick J Br J Cancer (1994) UK Exfol. cells TS-PCR only 73 12/61/0/0 91.8 63.0 20.5 26.0 16.4 2.7
Giannoudis A Int J Cancer (1999) UK Fixed
biopsies
GP5+/6+ 118 31/87/0/0 100.0 68.6 4.2 0.0 14.4 11.0 3.4 0.8 2.5 0.0 0.0 2.5 0.0 0.8 2.5
Herrington CS Br J Cancer (1995) UK Exfol. cells MY09/11 38 12/26/0/0 92.1 50.0 7.9 18.4 7.9
Southern SA Diagn Mol. Pathol (1998) UK Fixed
biopsies
GP5+/6+ 26 0/26/0/0 100.0 61.5 7.7 0.0 15.4 3.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.8
Europe sub-total 2271 406/1181/0/
684
87.1 52.6 6.5 1.7 10.5 8.4 2.6 2.4 2.6 0.3 2.5 1.5 0.6 0.8 1.6
North America
Sellors JW Can Med Assoc J. (2000) Canada Exfol. cells MY09/11 58 0/0/0/58 98.3 75.9 8.6 0.0 27.6 5.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Adam E Am J Obstet Gynecol (1998) USA Exfol. cells MY09/11 257 0/0/0/257 78.2 51.0 13.6 1.9 4.7 13.6
Aoyama C Diagn Mol. Pathol (1998) USA Fixed
biopsies
MY09/11 21 4/15/0/2 95.2 52.4 0.0 19.0 19.0
Schiff M Am J Epidemiol (2000) USA Exfol. cells MY09/11 112 70/42/0/0 77.7 17.0 4.5 1.8 22.3 4.5 16.1 4.5 4.5 4.5 12.5 4.5 2.7 6.3 9.8
North America sub-total 448 74/57/0/317 81.5 45.8 10.0 1.2 11.2 5.4 10.6 2.9 9.4 2.9 8.2 2.9 1.8 4.1 6.5
South/Central America
Abba MC International Papillomavirus
Conference Proceedings (2001)
Argentina Fixed
biopsies
MY09/11 86 13/24/0/49 97.7 50.0 14.0 7.0 2.3 7.0
Alonio LV Medicina (B Aires) (2000) Argentina Biopsies GP5+/6+ 36 0/36/0/0 80.6 41.7 11.1 0.0 5.6
Lorenzato F Int J Gynecol Cancer (2000) Brazil Exfol. cells MY09/11 60 0/0/0/60 86.7 56.7 3.3 3.3 3.3 8.3 10.0 0.0 1.7
Bosch Cancer Epidemiol
Biomarkers Prev (1993)
Colombia Exfol. cells MY09/11 125 0/125/0/0 63.2 32.8 0.0 2.4 2.4 1.6
Herrero R J Natl Cancer Inst (2000) Costa Rica Exfol. cells MY09/11 125 0/0/0/125 88.8 44.8 5.6 2.4 6.4 3.2 9.6 7.2 3.2 0.8 3.2 7.2 0.8 3.2 0.0
Ferrera A Int J Cancer (1999) Honduras Exfol. cells MY09/11 83 36/47/0/0 80.7 34.9 7.2 3.6 8.4 4.8 7.2 1.2 1.2 0.0 1.2 0.0 0.0 0.0 0.0
Rat