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The evolving definition of carcinogenic human papillomavirus

The evolving definition of carcinogenic human papillomavirus Thirteen human papillomavirus (HPV) genotypes have been judged to be carcinogenic or probably carcinogenic, and the cause of virtually all cervical cancer worldwide. Other HPV genotypes could possibly be involved. Although the inclusion of possibly carcinogenic HPV genotypes may hurt test specificity, it may indirectly increase the reassurance following a negative HPV test (i.e. the negative predictive value of an HPV test for cervical precancer and cancer). The future of cervical cancer screening in low-resource setting, however, may include once-in-a-lifetime, low-cost and rapid HPV testing. However, the tradeoff of more false positives for greater reassurance may not be acceptable if the local infrastructure cannot manage the screen positives. Now is the time for the community of scientists, doctors, and public health advocates to use the data presented at the 100th International Agency for Research on Cancer monograph meeting to rationally decide the target HPV genotypes for the next generation of HPV tests for use in high-resource and low- resource settings. The implications of including possibly HPV genotypes on HPV test performance, also for guidance on the use of these tests for cervical cancer prevention programs, are discussed. and 11) of the mucosotropic alpha genus. Schiffman et al. Commentary Periodically the International Agency for Research on in the accompanying article provide the rationale that was Cancer (IARC) convenes a meeting of cancer experts to used at the meeting to classify the mucosotropic HPV review and update the evidence regarding potential car- types as cancer-associated (carcinogenic) or not. Based on th cinogens. In February of 2009, the meeting for the 100 large case series, meta-analyses, and laboratory data of IARC monograph convened on the carcinogenicity of bio- mechanistic studies, twelve HPV genotypes (HPV16, 18, logical agents, including human papillomavirus (HPV), 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) were deemed now widely acknowledged as the obligate cause of cervical carcinogenic and HPV68 was considered probably carci- cancer and the important cause of other epithelial cancers, nogenic. th updating the evidence from the 90 monograph meeting in 2005 [1,2]. One of the primary goals of this meeting One of the important outcomes of the meeting was the was to examine the evidence for potential for each of the downgrading of HPV66 from the category of probably car- more than 100 HPV genotypes to cause cancer. The meet- cinogenic (Group 2A), as judged in 2005, to possibly car- ing report by Bouvard et al. [3] provides an overview of the cinogenic (Group 2B), which also includes HPV meeting for all biological agents and highlights that cervi- genotypes HPV26, HPV53, HPV67, HPV70, HPV73, and cal cancer is caused by HPV types that belong to a few phy- HPV82. As explained by Schiffman et al. [4,5], these HPV logenetically related "high-risk" species (apha-5, 6, 7, 9 genotypes had limited epidemiological evidence to cause Page 1 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 cancer but are genetically related to other HPV genotypes CIN2/3 cases are clinically important, i.e. have invasive that are carcinogenic. Unlike for HPV68, which is known potential, or not remains unclear. to maintain a cancer cell line (ME 180), there are as yet only scarce laboratory data showing carcinogenic proper- Future meetings will no doubt try to resolve whether these ties of few of the HPV genotypes classified as possibly car- borderline carcinogenic HPV genotypes (HPV26, HPV53, cinogenic (Group 2B) [3]. Furthermore, unfortunately, HPV66, HPV67, HPV70, HPV73, and HPV82) are cancer the available laboratory data did not provide information causing or not. Integrative epidemiologic and further lab- to understand the differences in carcinogenetic behavior oratory approaches will be needed for clarification. New between the HPV genotypes that belong to the "high-risk" investigative tools, such as micro-dissection of the lesion alpha species [6,7]. and HPV genotyping or in situ methods if they ever prove to be sufficiently sensitive, and genotype-specific detec- Temporarily categorizing HPV66 as probably carcino- tion of HPV E6/E7 transcripts or protein [11,12] may help genic during the four-year interval meetings impacted the to assign causal HPV genotypes. development of new clinical HPV assay. In 2005, there was only one FDA-approved HPV DNA test, hybrid cap- In the end, perhaps resolving this issue of which of the ture 2 (hc2; Qiagen (formerly Digene), Gaithersburg, borderline HPV genotypes are carcinogenic does not mat- Maryland, USA), which targets the 13 certain and proba- ter except for academic albeit important biological rea- bly carcinogenic HPV genotypes as a pool of HPV geno- sons: to understand the nature of HPV carcinogenicity and types. In 2009, one additional test, Cervista (Third Wave its relationship to viral genetics and phylogenetics [4]. We Technologies, Hologic, Inc., Madison, Wisconsin, USA), already know enough to decide which HPV genotypes to received FDA approval http://www.fda.gov/cdrh/mda/ include in clinical HPV tests. As shown by others [5] using docs/P080015.html and several other assays from other a receiver-operator curve (ROC)-like approach and CIN3 companies are being evaluated in clinical trials. Most have as the intermediate cancer endpoint, after including 8–10 included HPV66 in their panel of targeted HPV genotypes. most carcinogenic HPV genotypes there was only a slight increase in sensitivity and a larger cost in specificity with What is the impact of including HPV66 in clinical tests? each additional HPV genotype included. However, CIN3 The lifecycle of these tests, from development to valida- is subject to some diagnostic error [13,14], and some tion, is 10 years or more. As a consequence, there will be questionable or non-carcinogenic HPV genotypes can a generation of HPV tests (even some that are not now in cause CIN3 that has little potential for invasion [14]. clinical trials but too far along in the formulation phase to Thus, one would expect even greater clarity by redoing this alter) that include HPV66 and in theory will be slightly analysis with a cancer endpoint using the accumulated th less specific than what might otherwise be achieved. Thus, data presented at the 100 IARC monograph meeting. more women will test positive for HPV when used in pri- Experts then could come to a consensus about what is an mary screening or as triage/reflex test for equivocal (atyp- acceptable tradeoff in sensitivity versus specificity vis-à-vis ical squamous cells of undetermined significance [ASC- which HPV genotypes to include in clinical assays, accept- US]) cytology. ing the notion that no test will achieve perfect sensitivity and that poor specificity has important implications, Worldwide, the prevalence of HPV66 estimated to be including potential unnecessary treatment, which can 0.4% (95%CI = 0.3–0.4%) although there are some cause negative reproductive outcomes [15,16]. regional variations in its prevalence [8]. Therefore, an additional 1 in 250 all women screened (400 in 100,000 As a first approximation, a simple version of this ROC-like women) will be called carcinogenic HPV positive because analysis approach based on previously reported data of the inclusion of HPV66. For simplicity, the contribu- [8,17] is shown in Figure 1. Notably, as previously noted tion of HPV66 to testing positive has ignored the [5], there is very little gain in sensitivity after the inclusion unknown fraction of HPV66 positives co-infected with of the first ~10 HPV genotypes. Of note, the addition of carcinogenic and probable carcinogenic HPV genotypes. the possible HPV genotypes decreases specificity by Of those who are HPV66 positive, perhaps another = approximately 2%, or 2,000 additional HPV positives per 0.5% will have a concurrent diagnosis of cervical intraep- 100,000 women, with virtually no benefit. Notably, most ithelial grade 2 (CIN2), equivocal precancer [9,10], or of these possible HPV genotypes (HPV53, HPV66, CIN3, more certain precancer, both of which are typically HPV67, HPV70, HPV73, and HPV82) are commonly treated by excision or ablative procedures. Thus, the inclu- detected by hc2 as the result of less than perfect targeting sion of HPV66 will result in the identification of HPV66- of the carcinogenic and possibly carcinogenic HPV geno- related CIN2/3 in roughly 2 in 100,000 women screened types [18]. Despite the cross-reactivity to these weakly car- with the current HPV tests. Whether these HPV66-related cinogenic or non-carcinogenic HPV genotypes, hc2 has been proposed as the current benchmark for HPV test per- Page 2 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 gen Figure 1 Theo impact of addi types to a clinical ng i HPV ndividual carci assay nogenic, probable carcinogenic, and possible carcinogenic human papillomavirus (HPV) The impact of adding individual carcinogenic, probable carcinogenic, and possible carcinogenic human papillo- mavirus (HPV) genotypes to a clinical HPV assay. The impact of adding individual carcinogenic, probable carcinogenic, and possible carcinogenic human papillomavirus (HPV) genotypes to a clinical HPV assay was estimated using a receiver-opera- tor curve (ROC)-like approach of stepwise adding individual HPV genotypes according to their prevalence, from most preva- lent (HPV16) to least (HPV53), in cervical cancer [8,17]. Relative sensitivity (true positive fraction) was estimated based on those prevalences using the following assumptions: 1) HPV genotypes act independently such that cancers with multiple HPV genotypes detected were proportionally attributable to the HPV genotypes according to their overall prevalence; and 2) all cervical cancer is caused by HPV, and false negative results were independent of HPV genotype. Therefore, it was assumed that all cancers would have tested HPV positive with a perfectly sensitive test, and the relative contribution of each HPV genotype to cervical was a constant (although the absolute number increased). The relative false positive fraction, 1-Specificity, was esti- mated from the prevalence of individual HPV genotypes in the cytologic normal population, ignoring the overlap between HPV genotypes due to multi-HPV genotype infections (~25% of HPV positives). formance [19,20]. More fidelity for the important HPV these borderline HPV genotypes if there was downstream, genotypes will improve the performance of HPV tests by specific method of triaging HPV-positive women to sepa- reducing the number of false positive results. A more for- rate those in need of immediate colposcopy versus those th mal ROC-like analysis of the data from the 100 IARC who could be monitored by repeat screening in a year or monograph [3] is needed to confirm these observations. two. The key is good stratification of risk for cervical pre- cancer and cancer, and consistent, appropriate manage- The inclusion or exclusion of borderline carcinogenic ment of that risk [21]. Some approaches, such as using HPV genotypes in a clinical assay for carcinogenic HPV cytology [22], HPV genotyping [23], and/or p16 immu- becomes moot if robust strategies for management (risk nostaining [24], look promising but need further valida- stratification) of test positives become available. That is, tion. New, as of yet undiscovered, biomarkers may there would be no significant penalty to include some of provide still better solutions. Page 3 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 Although the inclusion of possibly carcinogenic HPV gen- In the end, it seems unlikely that companies that develop otypes may hurt test specificity, it may indirectly increase HPV tests will tailor their tests to individual country the reassurance following a negative HPV test i.e. the neg- needs. Now is the time for the community of scientists, ative predictive value of an HPV test for cervical precancer doctors, and public health advocates to use the data pre- th and cancer. Because non-carcinogenic and carcinogenic sented at the 100 IARC monograph meeting to rationally HPV infections alike are sexually transmitted, identifica- decide the target HPV genotypes for the next generation of tion of women with borderline carcinogenic or non-carci- HPV tests for use in high-resource and low-resource set- nogenic HPV identifies a subset of higher-risk women tings. And provide guidance on the use of these tests for who are more likely to subsequently acquire a new carci- cervical cancer prevention programs. However, the adop- nogenic HPV infection. That is, women who are HPV pos- tion of any cervical cancer screening and prevention pro- itive for any HPV type at any given time point represent a gram will depend on its social and cultural acceptance as sub-group that engages in more risky behavior, such as well as available resources and the political willpower to having more sexual partners, or have a partner(s) who is implement it. more likely to do so. Acknowledgements The author was supported by the Intramural Research Program of the NIH, The future of cervical cancer screening in low-resource set- National Cancer Institute. ting may include once-in-a-lifetime, low-cost and rapid HPV testing [25,26]. The inclusion/exclusion of HPV gen- References otypes, and therefore the tradeoff of sensitivity versus spe- 1. Human Papillomaviruses. [90]. In IARC Monographs on the Evalu- cificity, will depend greatly on the strategy for following- ation of Carcinogenic Risks to Humans Lyon, France, IARC; 2007. Ref up and managing the screen positives and the resources to Type: Serial (Book, Monograph) 2. Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F: do so. Prevention programs that will require the use of the Carcinogenicity of human papillomaviruses. Lancet Oncol 2005, more traditional screen, colposcopic evaluation of screen 6:204. 3. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El GF, et al.: A positives, and treatment of women with precancer will review of human carcinogens – Part B: biological agents. Lan- need sufficient numbers of highly-trained colposcopists cet Oncol 2009, 10:321-322. to handle the clinical volume of screen positives, which 4. Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Cecilia RA, et al.: The carcinogenicity of human papillomavirus could approach 10–15% of the population in many loca- types reflects viral evolution. Virology 2005, 20(337):76-84. tions [27]. The tradeoff of more false positives for greater 5. Schiffman M, Khan MJ, Solomon D, Herrero R, Wacholder S, Hild- esheim A, et al.: A study of the impact of adding HPV types to reassurance may not be an acceptable if the local infra- cervical cancer screening and triage tests. J Natl Cancer Inst structure cannot manage the screen positives. 2005, 97:147-150. 6. Hiller T, Poppelreuther S, Stubenrauch F, Iftner T: Comparative analysis of 19 genital human papillomavirus types with Other prevention programs may adopt screen and treat regard to p53 degradation, immortalization, phylogeny, and approaches, in which all screen positives undergo some epidemiologic risk classification. Cancer Epidemiol Biomarkers treatment. For example, HPV-positive women could then Prev 2006, 15:1262-1267. 7. Muench P, Hiller T, Probst S, Florea AM, Stubenrauch F, Iftner T: be evaluated by visual inspection with acetic acid to Binding of PDZ proteins to HPV E6 proteins does neither decide the best treatment option: chemotherapy or pallia- correlate with epidemiological risk classification nor with the immortalization of foreskin keratinocytes. Virology 2009. tive care for women with obvious cancer, surgical lesion 8. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, excision (by a physician at a regional medical center) for et al.: Worldwide prevalence and genotype distribution of large precancerous lesions that are not amenable to cryo- cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007, 7:453-459. therapy, and cryotherapy for all other HPV-positive 9. Castle PE, Stoler MH, Solomon D, Schiffman M: The Relationship women. Such an algorithm would only be applied to pop- of Community Biopsy-Diagnosed Cervical Intraepithelial Neoplasia Grade 2 to the Quality Control Pathology- ulations of older women, more than 10–15 years past the Reviewed Diagnoses:An ALTS Report. Am J Clin Pathol 2007, population median age of sexual debut, to minimize the 127:805-815. over-treatment of mostly transient HPV infections in 10. Castle PE, Schiffman M, Wheeler CM, Solomon D: Evidence for Frequent Regression of Cervical Intraepithelial Neoplasia- reproductive-age women. In general, because HPV-posi- Grade 2. Obstet Gynecol 2009, 113:18-25. tive women will not undergo any further characterizations 11. Spardy N, Duensing A, Charles D, Haines N, Nakahara T, Lambert PF, such as colposcopy or a secondary test, there should be a et al.: The human papillomavirus type 16 E7 oncoprotein acti- vates the Fanconi anemia (FA) pathway and causes acceler- greater emphasis on specificity i.e. inclusion of only the ated chromosomal instability in FA cells. J Virol 2007, certain carcinogenic HPV genotypes. However, there is 81:13265-13270. 12. Wang HK, Duffy AA, Broker TR, Chow LT: Robust production some evidence to suggest that cryotherapy provides a sec- and passaging of infectious HPV in squamous epithelium of ondary benefit of reducing the likelihood of acquiring primary human keratinocytes. Genes Dev 2009, 23:181-194. new HPV infections post-treatment [28], which might 13. Stoler MH, Schiffman M: Interobserver reproducibility of cervi- cal cytologic and histologic interpretations: realistic esti- increase the acceptability of over-treatment of screen pos- mates from the ASCUS-LSIL Triage Study. JAMA 2001, itives when applied once to a population. 285:1500-1505. 14. Castle PE, Cox JT, Jeronimo J, Solomon D, Wheeler CM, Gravitt PE, et al.: An analysis of high-risk human papillomavirus DNA- Page 4 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 negative cervical precancers in the ASCUS-LSIL Triage Study (ALTS). Obstet Gynecol 2008, 111:847-856. 15. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin- Hirsch P, et al.: Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 2008, 337:a1284. 16. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E: Obstetric outcomes after conservative treat- ment for intraepithelial or early invasive cervical lesions: sys- tematic review and meta-analysis. Lancet 2006, 367:489-498. 17. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al.: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007, 121:621-632. 18. Castle PE, Solomon D, Wheeler CM, Gravitt PE, Wacholder S, Schiff- man M: Human papillomavirus genotype specificity of hybrid capture 2. J Clin Microbiol 2008, 46:2595-2604. 19. Stoler MH, Castle PE, Solomon D, Schiffman M: The Expanded Use of HPV Testing in Gynecologic Practice per ASCCP-Guided Management Requires the Use of Well-Validated Assays. Am J Clin Pathol 2007, 127:1-3. 20. Meijer CJ, Berkhof J, Castle PE, Hesselink AT, Franco EL, Ronco G, et al.: Guidelines for human papillomavirus DNA test require- ments for primary cervical cancer screening in women 30 years and older. Int J Cancer 2009, 124:516-520. 21. Castle PE, Sideri M, Jeronimo J, Solomon D, Schiffman M: Risk assessment to guide the prevention of cervical cancer. J Low Genit Tract Dis 2008, 12:1-7. 22. Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al.: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screen- ing. J Natl Cancer Inst 2009, 101:88-99. 23. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al.: The elevated 10-year risk of cervical precancer and can- cer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clin- ical practice. J Natl Cancer Inst. 2005, 97(14):1072-1079. 24. Carozzi F, Confortini M, Palma PD, Del MA, Gillio-Tos A, De ML, et al.: Use of p16-INK4A overexpression to increase the specifi- city of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008. 25. Qiao YL, Sellors JW, Eder PS, Bao YP, Lim JM, Zhao FH, et al.: A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol 2008, 9:929-936. 26. Schiffman M, Wacholder S: From India to the world – a better way to prevent cervical cancer. N Engl J Med 2009, 360:1453-1455. 27. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, et al.: HPV screening for cervical cancer in rural India. N Engl J Med 2009, 360:1385-1394. 28. Wright T, Denny L, DeSousa M, Kuhn L: Durable benefits of HPV- based screen-and-treat to 36 months. 25th International Papillo- mavirus Conference 2009. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 5 of 5 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

The evolving definition of carcinogenic human papillomavirus

Castle, Philip
Infectious Agents and Cancer , Volume 4 (1) – May 11, 2009
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Copyright © 2009 by Castle; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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Abstract

Thirteen human papillomavirus (HPV) genotypes have been judged to be carcinogenic or probably carcinogenic, and the cause of virtually all cervical cancer worldwide. Other HPV genotypes could possibly be involved. Although the inclusion of possibly carcinogenic HPV genotypes may hurt test specificity, it may indirectly increase the reassurance following a negative HPV test (i.e. the negative predictive value of an HPV test for cervical precancer and cancer). The future of cervical cancer screening in low-resource setting, however, may include once-in-a-lifetime, low-cost and rapid HPV testing. However, the tradeoff of more false positives for greater reassurance may not be acceptable if the local infrastructure cannot manage the screen positives. Now is the time for the community of scientists, doctors, and public health advocates to use the data presented at the 100th International Agency for Research on Cancer monograph meeting to rationally decide the target HPV genotypes for the next generation of HPV tests for use in high-resource and low- resource settings. The implications of including possibly HPV genotypes on HPV test performance, also for guidance on the use of these tests for cervical cancer prevention programs, are discussed. and 11) of the mucosotropic alpha genus. Schiffman et al. Commentary Periodically the International Agency for Research on in the accompanying article provide the rationale that was Cancer (IARC) convenes a meeting of cancer experts to used at the meeting to classify the mucosotropic HPV review and update the evidence regarding potential car- types as cancer-associated (carcinogenic) or not. Based on th cinogens. In February of 2009, the meeting for the 100 large case series, meta-analyses, and laboratory data of IARC monograph convened on the carcinogenicity of bio- mechanistic studies, twelve HPV genotypes (HPV16, 18, logical agents, including human papillomavirus (HPV), 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) were deemed now widely acknowledged as the obligate cause of cervical carcinogenic and HPV68 was considered probably carci- cancer and the important cause of other epithelial cancers, nogenic. th updating the evidence from the 90 monograph meeting in 2005 [1,2]. One of the primary goals of this meeting One of the important outcomes of the meeting was the was to examine the evidence for potential for each of the downgrading of HPV66 from the category of probably car- more than 100 HPV genotypes to cause cancer. The meet- cinogenic (Group 2A), as judged in 2005, to possibly car- ing report by Bouvard et al. [3] provides an overview of the cinogenic (Group 2B), which also includes HPV meeting for all biological agents and highlights that cervi- genotypes HPV26, HPV53, HPV67, HPV70, HPV73, and cal cancer is caused by HPV types that belong to a few phy- HPV82. As explained by Schiffman et al. [4,5], these HPV logenetically related "high-risk" species (apha-5, 6, 7, 9 genotypes had limited epidemiological evidence to cause Page 1 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 cancer but are genetically related to other HPV genotypes CIN2/3 cases are clinically important, i.e. have invasive that are carcinogenic. Unlike for HPV68, which is known potential, or not remains unclear. to maintain a cancer cell line (ME 180), there are as yet only scarce laboratory data showing carcinogenic proper- Future meetings will no doubt try to resolve whether these ties of few of the HPV genotypes classified as possibly car- borderline carcinogenic HPV genotypes (HPV26, HPV53, cinogenic (Group 2B) [3]. Furthermore, unfortunately, HPV66, HPV67, HPV70, HPV73, and HPV82) are cancer the available laboratory data did not provide information causing or not. Integrative epidemiologic and further lab- to understand the differences in carcinogenetic behavior oratory approaches will be needed for clarification. New between the HPV genotypes that belong to the "high-risk" investigative tools, such as micro-dissection of the lesion alpha species [6,7]. and HPV genotyping or in situ methods if they ever prove to be sufficiently sensitive, and genotype-specific detec- Temporarily categorizing HPV66 as probably carcino- tion of HPV E6/E7 transcripts or protein [11,12] may help genic during the four-year interval meetings impacted the to assign causal HPV genotypes. development of new clinical HPV assay. In 2005, there was only one FDA-approved HPV DNA test, hybrid cap- In the end, perhaps resolving this issue of which of the ture 2 (hc2; Qiagen (formerly Digene), Gaithersburg, borderline HPV genotypes are carcinogenic does not mat- Maryland, USA), which targets the 13 certain and proba- ter except for academic albeit important biological rea- bly carcinogenic HPV genotypes as a pool of HPV geno- sons: to understand the nature of HPV carcinogenicity and types. In 2009, one additional test, Cervista (Third Wave its relationship to viral genetics and phylogenetics [4]. We Technologies, Hologic, Inc., Madison, Wisconsin, USA), already know enough to decide which HPV genotypes to received FDA approval http://www.fda.gov/cdrh/mda/ include in clinical HPV tests. As shown by others [5] using docs/P080015.html and several other assays from other a receiver-operator curve (ROC)-like approach and CIN3 companies are being evaluated in clinical trials. Most have as the intermediate cancer endpoint, after including 8–10 included HPV66 in their panel of targeted HPV genotypes. most carcinogenic HPV genotypes there was only a slight increase in sensitivity and a larger cost in specificity with What is the impact of including HPV66 in clinical tests? each additional HPV genotype included. However, CIN3 The lifecycle of these tests, from development to valida- is subject to some diagnostic error [13,14], and some tion, is 10 years or more. As a consequence, there will be questionable or non-carcinogenic HPV genotypes can a generation of HPV tests (even some that are not now in cause CIN3 that has little potential for invasion [14]. clinical trials but too far along in the formulation phase to Thus, one would expect even greater clarity by redoing this alter) that include HPV66 and in theory will be slightly analysis with a cancer endpoint using the accumulated th less specific than what might otherwise be achieved. Thus, data presented at the 100 IARC monograph meeting. more women will test positive for HPV when used in pri- Experts then could come to a consensus about what is an mary screening or as triage/reflex test for equivocal (atyp- acceptable tradeoff in sensitivity versus specificity vis-à-vis ical squamous cells of undetermined significance [ASC- which HPV genotypes to include in clinical assays, accept- US]) cytology. ing the notion that no test will achieve perfect sensitivity and that poor specificity has important implications, Worldwide, the prevalence of HPV66 estimated to be including potential unnecessary treatment, which can 0.4% (95%CI = 0.3–0.4%) although there are some cause negative reproductive outcomes [15,16]. regional variations in its prevalence [8]. Therefore, an additional 1 in 250 all women screened (400 in 100,000 As a first approximation, a simple version of this ROC-like women) will be called carcinogenic HPV positive because analysis approach based on previously reported data of the inclusion of HPV66. For simplicity, the contribu- [8,17] is shown in Figure 1. Notably, as previously noted tion of HPV66 to testing positive has ignored the [5], there is very little gain in sensitivity after the inclusion unknown fraction of HPV66 positives co-infected with of the first ~10 HPV genotypes. Of note, the addition of carcinogenic and probable carcinogenic HPV genotypes. the possible HPV genotypes decreases specificity by Of those who are HPV66 positive, perhaps another = approximately 2%, or 2,000 additional HPV positives per 0.5% will have a concurrent diagnosis of cervical intraep- 100,000 women, with virtually no benefit. Notably, most ithelial grade 2 (CIN2), equivocal precancer [9,10], or of these possible HPV genotypes (HPV53, HPV66, CIN3, more certain precancer, both of which are typically HPV67, HPV70, HPV73, and HPV82) are commonly treated by excision or ablative procedures. Thus, the inclu- detected by hc2 as the result of less than perfect targeting sion of HPV66 will result in the identification of HPV66- of the carcinogenic and possibly carcinogenic HPV geno- related CIN2/3 in roughly 2 in 100,000 women screened types [18]. Despite the cross-reactivity to these weakly car- with the current HPV tests. Whether these HPV66-related cinogenic or non-carcinogenic HPV genotypes, hc2 has been proposed as the current benchmark for HPV test per- Page 2 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 gen Figure 1 Theo impact of addi types to a clinical ng i HPV ndividual carci assay nogenic, probable carcinogenic, and possible carcinogenic human papillomavirus (HPV) The impact of adding individual carcinogenic, probable carcinogenic, and possible carcinogenic human papillo- mavirus (HPV) genotypes to a clinical HPV assay. The impact of adding individual carcinogenic, probable carcinogenic, and possible carcinogenic human papillomavirus (HPV) genotypes to a clinical HPV assay was estimated using a receiver-opera- tor curve (ROC)-like approach of stepwise adding individual HPV genotypes according to their prevalence, from most preva- lent (HPV16) to least (HPV53), in cervical cancer [8,17]. Relative sensitivity (true positive fraction) was estimated based on those prevalences using the following assumptions: 1) HPV genotypes act independently such that cancers with multiple HPV genotypes detected were proportionally attributable to the HPV genotypes according to their overall prevalence; and 2) all cervical cancer is caused by HPV, and false negative results were independent of HPV genotype. Therefore, it was assumed that all cancers would have tested HPV positive with a perfectly sensitive test, and the relative contribution of each HPV genotype to cervical was a constant (although the absolute number increased). The relative false positive fraction, 1-Specificity, was esti- mated from the prevalence of individual HPV genotypes in the cytologic normal population, ignoring the overlap between HPV genotypes due to multi-HPV genotype infections (~25% of HPV positives). formance [19,20]. More fidelity for the important HPV these borderline HPV genotypes if there was downstream, genotypes will improve the performance of HPV tests by specific method of triaging HPV-positive women to sepa- reducing the number of false positive results. A more for- rate those in need of immediate colposcopy versus those th mal ROC-like analysis of the data from the 100 IARC who could be monitored by repeat screening in a year or monograph [3] is needed to confirm these observations. two. The key is good stratification of risk for cervical pre- cancer and cancer, and consistent, appropriate manage- The inclusion or exclusion of borderline carcinogenic ment of that risk [21]. Some approaches, such as using HPV genotypes in a clinical assay for carcinogenic HPV cytology [22], HPV genotyping [23], and/or p16 immu- becomes moot if robust strategies for management (risk nostaining [24], look promising but need further valida- stratification) of test positives become available. That is, tion. New, as of yet undiscovered, biomarkers may there would be no significant penalty to include some of provide still better solutions. Page 3 of 5 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:7 http://www.infectagentscancer.com/content/4/1/7 Although the inclusion of possibly carcinogenic HPV gen- In the end, it seems unlikely that companies that develop otypes may hurt test specificity, it may indirectly increase HPV tests will tailor their tests to individual country the reassurance following a negative HPV test i.e. the neg- needs. Now is the time for the community of scientists, ative predictive value of an HPV test for cervical precancer doctors, and public health advocates to use the data pre- th and cancer. Because non-carcinogenic and carcinogenic sented at the 100 IARC monograph meeting to rationally HPV infections alike are sexually transmitted, identifica- decide the target HPV genotypes for the next generation of tion of women with borderline carcinogenic or non-carci- HPV tests for use in high-resource and low-resource set- nogenic HPV identifies a subset of higher-risk women tings. And provide guidance on the use of these tests for who are more likely to subsequently acquire a new carci- cervical cancer prevention programs. However, the adop- nogenic HPV infection. That is, women who are HPV pos- tion of any cervical cancer screening and prevention pro- itive for any HPV type at any given time point represent a gram will depend on its social and cultural acceptance as sub-group that engages in more risky behavior, such as well as available resources and the political willpower to having more sexual partners, or have a partner(s) who is implement it. more likely to do so. Acknowledgements The author was supported by the Intramural Research Program of the NIH, The future of cervical cancer screening in low-resource set- National Cancer Institute. ting may include once-in-a-lifetime, low-cost and rapid HPV testing [25,26]. The inclusion/exclusion of HPV gen- References otypes, and therefore the tradeoff of sensitivity versus spe- 1. Human Papillomaviruses. [90]. In IARC Monographs on the Evalu- cificity, will depend greatly on the strategy for following- ation of Carcinogenic Risks to Humans Lyon, France, IARC; 2007. Ref up and managing the screen positives and the resources to Type: Serial (Book, Monograph) 2. Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F: do so. Prevention programs that will require the use of the Carcinogenicity of human papillomaviruses. Lancet Oncol 2005, more traditional screen, colposcopic evaluation of screen 6:204. 3. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El GF, et al.: A positives, and treatment of women with precancer will review of human carcinogens – Part B: biological agents. Lan- need sufficient numbers of highly-trained colposcopists cet Oncol 2009, 10:321-322. to handle the clinical volume of screen positives, which 4. Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Cecilia RA, et al.: The carcinogenicity of human papillomavirus could approach 10–15% of the population in many loca- types reflects viral evolution. Virology 2005, 20(337):76-84. tions [27]. The tradeoff of more false positives for greater 5. Schiffman M, Khan MJ, Solomon D, Herrero R, Wacholder S, Hild- esheim A, et al.: A study of the impact of adding HPV types to reassurance may not be an acceptable if the local infra- cervical cancer screening and triage tests. J Natl Cancer Inst structure cannot manage the screen positives. 2005, 97:147-150. 6. Hiller T, Poppelreuther S, Stubenrauch F, Iftner T: Comparative analysis of 19 genital human papillomavirus types with Other prevention programs may adopt screen and treat regard to p53 degradation, immortalization, phylogeny, and approaches, in which all screen positives undergo some epidemiologic risk classification. Cancer Epidemiol Biomarkers treatment. For example, HPV-positive women could then Prev 2006, 15:1262-1267. 7. Muench P, Hiller T, Probst S, Florea AM, Stubenrauch F, Iftner T: be evaluated by visual inspection with acetic acid to Binding of PDZ proteins to HPV E6 proteins does neither decide the best treatment option: chemotherapy or pallia- correlate with epidemiological risk classification nor with the immortalization of foreskin keratinocytes. Virology 2009. tive care for women with obvious cancer, surgical lesion 8. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, excision (by a physician at a regional medical center) for et al.: Worldwide prevalence and genotype distribution of large precancerous lesions that are not amenable to cryo- cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007, 7:453-459. therapy, and cryotherapy for all other HPV-positive 9. Castle PE, Stoler MH, Solomon D, Schiffman M: The Relationship women. Such an algorithm would only be applied to pop- of Community Biopsy-Diagnosed Cervical Intraepithelial Neoplasia Grade 2 to the Quality Control Pathology- ulations of older women, more than 10–15 years past the Reviewed Diagnoses:An ALTS Report. Am J Clin Pathol 2007, population median age of sexual debut, to minimize the 127:805-815. over-treatment of mostly transient HPV infections in 10. 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Published: May 11, 2009

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