Correspondence
Human Papillomaviruses and Anogenital Cancer
N Engl J Med 1998; 338:921-922March 26, 1998
- Article
To the Editor:
The November 6 issue of the Journal contained two articles1,2 and an editorial3 that highlighted the complex relation between human papillomaviruses (HPVs), human immunodeficiency virus (HIV), and anogenital cancer. As Frisch et al.2 noted, the strong epidemiologic association between sexual behavior, HPVs, and cervical neoplasia has been recognized for some time, and as Dr. Shah adds in the editorial,3 a similar link with anal cancer had been suggested from other studies as well. Although the link between sexual behavior, HPV infection, and anogenital cancer is strong, there are clearly other factors of equal or greater importance, because many more people are infected with HPVs than have cancer. To view these malignant conditions as simply being caused by sexually transmitted infections, as implied in the title of the article by Frisch et al.2 and as emphasized in the editorial, is misleading. In the context of a multifactorial disease, attributing cause to one recognized infectious step in the process has the potential to confuse clinicians and arouse undue fear in the general population. We would urge caution in the use of terms such as “cause,” which can be overinterpreted. We believe public health is best served by the more difficult approach involving education about the multifactorial nature of risk associated with disease.
There is also a complex relation between HIV and HPVs. The article by Sun et al.,1 although failing to cite our 1994 study,4 reaches an identical conclusion: that HIV-seropositive women with low CD4 cell counts are more likely to have persistent HPV infection. Since persistent HPV infection has been associated with an increased risk of premalignant disease in some populations,5,6 the authors conclude that persistent HPV infection may explain the increased incidence of cervical intraepithelial neoplasia in HIV-seropositive women. Although they collected the data to answer this question (i.e., Pap smears at each visit), they did not provide their results and therefore missed the opportunity to test their hypothesis and contribute new information.
6 ReferencesSuzanne D. Vernon, Ph.D.
Elizabeth R. Unger, Ph.D., M.D.
William C. Reeves, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 303331
Sun X-W ,Kuhn L ,Ellerbrock TV ,Chiasson MA ,Bush TJ ,Wright TC Jr . Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 1997;337:1343-1349
Full Text | Web of Science | Medline2
Frisch M ,Glimelius B ,van den Brule AJC , et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997;337:1350-1358
Full Text | Web of Science | Medline3
Shah KV . Human papillomaviruses and anogenital cancers. N Engl J Med 1997;337:1386-1388
Full Text | Web of Science | Medline4
Vernon SD ,Reeves WC ,Clancy KA , et al. A longitudinal study of human papillomavirus DNA detection in human immunodeficiency virus type 1-seropositive and -seronegative women. J Infect Dis 1994;169:1108-1112
CrossRef | Web of Science | Medline5
Koutsky LA ,Holmes KK ,Critchlow CW , et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 1992;327:1272-1278
Full Text | Web of Science | Medline6
Ho GY ,Burk RD ,Klein S , et al. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst 1995;87:1365-1371
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree that the word “cause” should not be used haphazardly, but Vernon et al. create unnecessary confusion about terminology. We maintain, on the basis of our data and the relevant literature, that HPVs appear convincingly to be a cause of anal cancer. The following are among the central criteria used to define an agent as a cause of a disease: the presence of the agent incurs an increase in the occurrence of disease, and elimination of the agent is followed by a decrease in the incidence of disease. Although data from prospective studies strongly implicate HPVs in anogenital neoplasia, we must await prophylactic vaccine trials to determine whether the second of these criteria is met. If HPVs are truly and necessarily involved, as discussed by Shah — that is, if these viruses constitute a necessary cause of squamous-cell variants of anogenital cancers — then it would obviously be wrong to regard other contributing causes as being “of equal or greater importance.” By analogy, no matter how closely other contributing factors may be associated with clinical tuberculosis, it would be incorrect — and confusing — to regard such contributing causes as potentially more important than the mycobacterium itself. Following the line of argument of Vernon et al.: other factors involved in lung cancer may be of equal or greater importance than tobacco smoking, since most smokers never have lung cancer, and the extreme consequence of this view would be that smoking should no longer be termed a cause of lung cancer.
Morten Frisch, M.D., Ph.D.
Statens Serum Institut, DK-2300 Copenhagen S, DenmarkHans-Olov Adami, M.D., Ph.D.
Karolinska Institute, S-17177 Stockholm, SwedenMads Melbye, M.D., Ph.D.
Statens Serum Institut, DK-2300 Copenhagen S, DenmarkAuthor/Editor Response
Although the pathogenesis of invasive cervical cancer is multifactorial, there are extensive epidemiologic data linking HPV to invasive carcinomas of the cervix, penis, vagina, and anus. HPV DNA can be detected in over 90 percent of invasive cervical cancers, and although more than 30 different types of HPV infect the anogenital tract, the majority of invasive cervical cancers worldwide are associated with HPV-16 or HPV-18.1 In addition, certain types of HPV are associated with specific histologic forms of cervical cancer. HPV-16 and HPV-18 are the types most commonly found in association with invasive squamous-cell carcinomas and adenocarcinomas of the cervix, respectively. There are also extensive laboratory data linking HPV to invasive cervical cancer. The HPV genome encodes two oncoproteins, E6 and E7, that can transform many types of cells in vitro, and continued expression of these oncoproteins is necessary for the maintenance of the transformed phenotype.2 Moreover, introduction of antisense RNA directed against HPV E6 or E7 causes cultured human cervical-carcinoma cells to revert to a nontransformed phenotype.3 Consequently, the World Health Organization has classified HPV-16 and HPV-18 as known human carcinogens.2,4 From a public health perspective, establishing a causal relation between HPV and invasive anogenital cancer is extremely important because it highlights the need to develop an HPV vaccine to prevent preinvasive and invasive anogenital disease.
Persistence of HPV shedding is a poorly understood phenomenon that may have important biologic implications. We used a highly sensitive polymerase-chain-reaction method to detect HPV, described the natural history of HPV shedding over a multiyear period in a large cohort of HIV-seropositive and HIV-seronegative women, and carefully ruled out the presence of squamous intraepithelial lesions in subjects at entry into the study using colposcopy. Since squamous intraepithelial lesions are associated with persistent HPV shedding in women in the general population, and these lesions are about five times more common in HIV-seropositive women, ruling out their presence is essential for interpreting studies that compare HPV shedding in HIV-seropositive and HIV-seronegative women.5 Because of the potential importance of the persistence of HPV and the dramatic difference that we observed in persistence between HIV-seropositive and HIV-seronegative women, additional analyses are under way using data from the New York Cervical Disease Study to determine the effect of HIV seropositivity and the persistence of HPV on the incidence of squamous intraepithelial lesions and invasive cervical cancer.
5 ReferencesTedd V. Ellerbrock, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333Louise Kuhn, Ph.D.
Thomas C. Wright, Jr., M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 100321
Bosch FX ,Manos MM ,Munoz N , et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87:796-802
CrossRef | Web of Science | Medline2
Park TW ,Fujiwara H ,Wright TC . Molecular biology of cervical cancer and its precursors. Cancer 1995;76:Suppl:1902-1913
CrossRef | Web of Science | Medline3
Hu B ,Liu W ,Hanania EG ,Fu S ,Wang T ,Deisseroth AB . Suppression of tumorigenesis by transcription units expressing the antisense E6 and E7 messenger RNA (mRNA) for the transforming proteins of the human papillomavirus and the sense mRNA for the retinoblastoma gene in cervical carcinoma cells. Cancer Gene Ther 1995;2:19-32
Web of Science | Medline4
Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 64. Lyon, France: International Agency for Research on Cancer, 1995.
5
Wright TC Jr ,Ellerbrock TV ,Chiasson MA ,Van Devanter N ,Sun XW . Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. Obstet Gynecol 1994;84:591-597
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Juan Carlos Feoli-Fonseca, Luc L. Oligny, Pierre Brochu, Pierre Simard, Sarah Falconi, Wagner V. Yotov. (2001) Human papillomavirus (HPV) study of 691 pathological specimens from Quebec by PCR-direct sequencing approach. Journal of Medical Virology 63:4, 284-292
CrossRef
