BMJ No 7109 Volume 315
Editorial Saturday 13 September 1997
Is human papillomavirus an infectious cause of non-cervical anogenital tract cancers?
Results from a large study provide strong epidemiological evidence
See p 646"
In cervical cancers human papillomavirus DNA can be detected in over
90% of lesions. Moreover, cervical human papillomavirus has been
detected before the development of cervical intraepithelial neoplasia,
which is well established to be a precursor of cancer.(2) In
non-cervical anogenital tumours a common causal relation with human
papillomavirus is suggested by the raised risk of anal, vulvar, and
vaginal tumours after cervical cancer(3); a high prevalence
of penile intraepithelial neoplasia in the sexual partners of women
with cervical intraepithelial neoplasia(4); and the high
prevalence of human papillomavirus DNA in non-cervical anogenital
cancer tissues.(5) Infection of normal non-cervical
anogenital epithelium may be as common as in the
cervix.(6)
The researchers conducted a nested case-control investigation of
the seroprevalence of human papillomavirus antibodies and subsequent
anogenital tumours in Finland and Norway by matching data in the cancer
registries in the two countries to nearly 700 000 subjects who had
provided stored blood samples at various earlier times.
The pre-disease
specimens were tested for IgG to virus-like particles of human
papillomavirus 16, 18, and 33-three types commonly detected in
specimens from anogenital tumours. They tested 81 patients with
non-cervical anogenital cancer and 240 matched controls. Human
papillomavirus antibodies, but not antibodies to another sexually
transmitted infection-Chlamydia trachomatis, were more
common in people who later developed anogenital cancers, including
vulvar, vaginal, and penile cancers. Anal cancer, however, was not
related to seroprevalence of these three types of human papillomavirus.
The findings suggest that human papillomavirus infection is associated
with later diagnosis of vulvar, vaginal, and penile cancers. This
inference is further reinforced by the consistency of these findings
with results from prospective human papillomavirus serological studies
of patients who later developed cervical cancer.(8, 9) There
are caveats, however. In the investigation by Bjørge et al only the
results in vulvar and vaginal cancer were statistically significant,
and the absence of an anti-human papillomavirus IgG association with
anal cancer was not explained-although it may have been due to a
chance increase in seroprevalence among the small group of matched
controls. It would also have been useful to know whether the cases
positive for human papillomavirus antibody developed tumours containing
DNA of the same types as implicated by serology. In addition,
consideration of pathological subtypes of cancers in an investigation
with longer follow up is needed. For example, warty and basaloid vulvar
tumours in younger women are generally associated with human
papillomavirus, but not the typical keratinising carcinomas of older
women.(10) Lastly, repeated observations over time, rather
than a single serological result for each patient, would further
confirm these causal relations. Nevertheless, given the rarity of
non-cervical anogenital tumours and the general unavailability of large
collections of prospectively stored specimens, it is unlikely that many
other research groups could expand considerably on these results. Thus,
Bjørge et al have provided an important and difficult to obtain piece
of evidence demonstrating the probable relation between human
papillomavirus infection and later development of non-cervical
anogenital cancers.
Prospective and large population based studies like this show that
human papillomavirus serology is an increasingly useful biomarker. Its
sensitivity and specificity are not optimal, however. For example, only
about half the women positive for cervical human papillomavirus 16 DNA
are antibody positive.(11) Therefore, human papillomavirus
seroassays remain primarily epidemiological research tools. Overall,
the major public health importance of the findings by Bjørge et al is
that a successful human papillomavirus vaccine could have benefits
beyond the primary goal of preventing cervical cancer.
Howard D Strickler
Mark H Schiffman
References
1 Hill AB. The environment and disease: association or
causation. Proc R Soc Med 1965;58:295.
2 IARC Working Group. Monographs on the evaluation of
carcinogenic risks to humans. Vol 64. Human
papillomaviruses. Lyon: IARC, 1996.
3 Rabkin CS, Biggar RJ, Melbye M, Curtis RE. Second primary
cancers following anal and cervical carcinoma: evidence of shared
etiologic factors. Am J Epidemiol 1992;136:54-8.
4 Barrasso R, De Brux J, Croissant O, Orth G. High prevalence of
papillomavirus-associated penile intraepithelial neoplasia in sexual
partners of women with cervical intraepithelial neoplasia. N
Engl J Med 1987;317:916-23.
5 Schneider A, Meinhardt G, Kirchmayr R, Schneider V. Prevalence
of human papillomavirus genomes in tissues from the lower genital tract
as detected by molecular in situ hybridization. Int J Gynecol
Pathol 1991;10:1-14.
6 Bauer HM, Ting Y, Greer CE, Chambers JC, Tashiro CJ, Chimera
J, et al. Genital human papillomavirus infection in female university
students as determined by a PCR-based method. JAMA
1991;265:472-7.
7 Bjørge T, Dillner J, Anttila T, Engeland A, Hakulinen T,
Jellum E, et al. A prospective seroepidemiological study of the role of
human papillomavirus in non-cervical anogenital cancers.
BMJ 1997;315:646-9.
8 Lehtinen M, Dillner J, Knekt P, Loustarinen T, Aromaa A,
Kirnbauer R, et al. Serologically diagnosed infection with human
papillomavirus type 16 and risk for subsequent development of cervical
cancer: nested case-control study. BMJ 1996;312:537-9.
9 Shah KV, Viscidi RP, Alberg AJ, Helzlsouer KJ, Comstock CW.
Antibodies to human papillomavirus 16 and subsequent in situ or
invasive cancer of the cervix. Cancer Epidemiology Biomarkers
and Prevention (in press).
10 Kurman RJ, Toki T, Schiffman MH. Basaloid and warty carcinomas
of the vulva. Am J Surg Pathol 1993;17:133-45.
11 Kirnbauer R, Hubbert NL, Wheeler CM, Becker TM, Lowy DR,
Schiller JT. A virus-like particle enzyme-linked immunosorbent assay
detects serum antibodies in a majority of women infected with human
papillomavirus type 16. J Natl Cancer Inst
1994;86:494-9.
Human papillomavirus
Thus, the anogenital tract can be considered to be a generally
susceptible region for epithelial human papillomavirus infections, with
each local area a potential viral reservoir and source of
autoinoculations. Human papillomavirus infection of the cervical
transformation zone, however, produces the major burden of anogenital
cancers. Indeed, non-cervical anogenital cancers are rare, and tissue
specimens from before the development of non-cervical anogenital
neoplasia are not generally available from prospective studies of human
papillomavirus infection. Using recently validated serological methods,
Bjørge et al, in this edition of the BMJ, present the first
major study to examine the relation of exposure to human papillomavirus
to the later development of non-cervical anogenital
cancers.(7)
Senior clinical investigator
Viral Epidemiology Branch
Chief interdisciplinary studies section
Environmental Epidemiology Branch,
National Cancer Institute,
Bethesda,
Md 20892, USA
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