Human papillomaviruses (HPVs) are a diverse group of small DNA tumor viruses that infect the mucosal and cutaneous epithelia.1 The largest and most clinically relevant of the HPV genera, α-papillomaviruses, includes the “α-mucosal” types that infect mucosal squamous surfaces and are among the most common sexually transmitted infections.1,2 According to the classification of the International Agency for Research on Cancer,3 12 α-mucosal HPV types are considered carcinogenic (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), 1 type (HPV-68) to be probably carcinogenic, and 12 others (26, 53, 66, 67, 70, 73, 82, 30, 34, 69, 85, 97) possibly carcinogenic.
Human papillomavirus types considered to be “low-risk” (LR HPV) are not classified as carcinogens or possible carcinogens and are only rarely found in cancer specimens.4,5 There are more than 30 α-mucosal LR HPV types, including types 6, 11, 40, 42, 44, 54, 61, 72, 81, and 89.4 Infection with LR HPV has important clinical implications because these types are associated with low-grade disease at anogenital sites (cervical, vaginal, vulvar, penile, and anal intraepithelial neoplasias).6–9 Low-risk HPV types 6 and 11 are also associated with almost all HPV-positive cases of recurrent respiratory papillomatosis.10,11 Furthermore, LR HPV types 6 and 11 cause up to 90% of anogenital warts12–14; extensive systematic reviews indicate anogenital warts represent a highly prevalent disease associated with significant psychological burden and substantial healthcare costs.15,16
There is a growing body of evidence implying an association of LR HPV with an increased risk of cancers, among individuals with a history of anogenital warts. In addition, a possible role of LR HPV in potentiation of coinfections with other pathogenic agents has been suggested. The present review discusses and critically appraises the available evidence for these potential pathogenic roles of LR HPV.
Anogenital Warts and Risk of Cancer
In the 1970s, several publications reported detection of HPV particles or DNA in a substantial proportion of vulvar and cervical tumors. Case series reports of malignant transformation of anogenital warts were also published.17 These findings led to 2 lines of inquiry: prospective studies using national registries of cancer incidence and risk among men and women after a diagnosis of anogenital warts, and case-control studies assessing possible association between anogenital warts and risk of vulvar and penile cancers.
In the first of the registry-based prospective studies (1991),18 male patients with a prior diagnosis of anogenital warts had a marginally significantly elevated incidence of cancer at all sites, as documented in the Swedish Cancer Registry (risk ratio [RR], 1.6; 95% confidence interval [CI], 1.0–2.5). Furthermore, male patients had an increased incidence of genitourinary cancers (including cancers of the prostate, testis, penis, kidney, ureter, bladder, and urethra; RR, 2.6; 95% CI, 1.2–5.0). No significant increased cancer risk was observed among women. However, the total study population included was relatively small and consisted primarily of men. In a subsequent larger study of women published in 1997,19 prior diagnosis of anogenital warts was associated with increased incidence of vulvar (standardized incidence ratio [SIR], 40.1; 95% CI, 20.0–71.7) and cervical cancers (SIR, 2.0; 95% CI, 1.3–3.0). Anal cancer (SIR, 8.5; 95% CI, 0.9–30.5) and cervical carcinoma in situ (SIR, 2.6; 95% CI, 2.3–2.9) lesions also showed marginally significant increased incidence. Interestingly, significantly elevated incidences of lung (SIR, 3.8; 95% CI, 2.2–6.0), urinary bladder (SIR, 3.7; 95% CI, 1.2–8.6), and all smoking-related cancers combined (cancers of the mouth, oropharynx and hypopharynx, esophagus, pancreas, larynx, lung, renal pelvis, and urinary bladder; SIR, 3.1; 95% CI, 2.1–4.6) were reported. Notably, laboratory investigations support biological plausibility for an interaction between smoking and progression of HPV infection to carcinogenesis.20 Processes involved may include suppression of immune function, leading to persistence of HPV infection,21,22 impairment of cellular ability to recover from mutagenic insults,23 and possibly increased cellular integration of HPV into the DNA of smokers.24 More research is needed to elucidate the underlying biological mechanism of the observation that a history of genital warts increases subsequent risk of developing a smoking-related cancer.
In 2006, investigators from Sweden25 studied 10,971 patients hospitalized with a diagnosis of genital warts between 1965 and 1999. Patients were followed up for a median of 13 years. Anogenital warts were associated with elevated incidence of vulvar and vaginal cancers, as well as cervical carcinoma in situ among women and penile cancer among men. Elevated incidence of lung cancer in both men and women was observed, as well as excess risks of buccal cancer, nonmelanoma skin cancer, and Hodgkin and non–Hodgkin lymphoma. In the largest study to date,26 of 50,000 Danish men and women who received a diagnosis of genital warts during 1978 to 2008, significantly elevated total cancer incidence of SIR (1.3; 95% CI, 1.3–1.4) was observed among patients diagnosed as having anogenital warts compared with the general population. Increased incidence of cancers of the mouth, tonsils, lung, lymphomas, and nonmelanoma skin cancer was also observed. Among women, significantly elevated risks of cervical, vulvar, vaginal, and anal cancers were reported; highest RRs were for vulvar cancers (SIR, 14.8; 95% CI, 11.7–18.6) and anal cancers (SIR, 7.8; 95% CI, 5.4–11.0). Even higher RRs of 21.5 (95% CI, 14.4–30.9) for anal cancer and 8.2 (95% CI, 4.1–14.6) for penile cancer were observed among men. In case-control studies, anogenital warts have been associated with elevated risks of cervical neoplasia,27 vulvar cancer17,28 penile cancer,29,30 and vaginal high-grade squamous intraepithelial lesions31; marginal associations with vaginal cancer were reported in one study.28
Although prospective and case-control studies consistently reported higher risk of anogenital cancers among men and women with a history of anogenital warts, caution must be taken in interpreting these results. Most studies did not directly assess HPV-6/11 in the tumors. In the few studies that did report tumor HPV status,29,31 prevalence of HPV type 6/11 single infections was rare. In the case-control study of vaginal cancer,31 only 1 of 74 cases of vaginal carcinoma in situ, and 0 of 25 vaginal cancer tumors, had a single HPV-6/11 infection. Most HPV-6/11 infections were detected as multiple infections with high-risk (HR) HPV types (e.g., HPV-16/18). In the Danish penile cancer study, only 1 (3%) of 71 tumors harbored LR HPV (positive for HPV-6).29 Finally, in a recent report specifically designed to investigate the potential role of LR HPV types in the development of verrucous carcinoma,32 a cancer suspected to evolve from genital warts, few had any detectable LR HPV types, and none had evidence of these types alone. No specimen of giant genital warts (the presumed precursor lesion to cancer) tested positive for p16INK4A, a marker of transforming HPV infections.33
An additional consideration is the possibility that treatment of anogenital warts may have a role in carcinogenesis. In particular, the topical application of crude podophyllin resin to the murine cervix is documented to cause changes resembling carcinoma in situ.34,35 In another investigation of 18 mice,36 prolonged cervical application of podophyllin (twice weekly for 15 months), resulted in one case of epidermal carcinoma. Contrasting with these findings, other published animal studies have found podofilox, the purified form of the main active ingredient, not to be carcinogenic.37–39 Trichloroacetic acid, a caustic agent used for local treatment of genital warts, is classed as possibly carcinogenic to humans.40 Studies of male and female mice have shown that administration of trichloroacetic acid via drinking water increased the incidences of hepatocellular adenomas and carcinomas. However, no published studies in animals or humans have investigated carcinogenicity of tricholoroacetic acid administered to skin or mucous membranes. The information currently available is not sufficient to determine whether trichloroacetic acid is carcinogenic to humans.40
Thus, although anogenital warts may seem to predispose men and women to a higher incidence of anogenital and other cancers, a direct role of the LR HPV types in subsequent cancer risk is unlikely. Increased cancer risk associated with anogenital warts may be due to a shared exposure, namely, concomitant exposure and infection with HR HPV types. Indeed, in a multinational prospective study of men, HPV-16/18 were co-detected with HPV-6/11 in 12.5% of anogenital warts.41 It is unclear whether shared exposure or behavior also explains the observed elevated risk of non-genital cancers. Alternatively, individuals with a prior diagnosis of anogenital warts may have other exposures that increase risk of carcinogenesis, an underlying immune impairment, or other inherent genetic susceptibility that increases cancer risk. Studies examining the biological mechanisms underlying these observations are needed. Furthermore, as noted above, some treatments for warts have been associated with increased risk of carcinogenesis. Although unproven, this may also contribute to the increased risk of cancer among those with a history of anogenital warts.
Potentiation of Coinfections: Role in HIV Acquisition
Sexually transmitted infections may be associated with disruption of the anogenital epithelium, allowing HIV greater access to target cells within the epithelium and underlying tissues. They may also induce an immune response resulting in an influx of HIV-susceptible immune cells into the epithelium, which in combination with a friable epithelium may increase the risk of HIV infection.
A growing body of evidence suggests that HPV infection is associated with increased risk of HIV infection. In particular, several studies have examined the role of HPV infection in HIV acquisition in sub-Saharan Africa. A systematic review42 reported strong, consistent associations between prevalent HPV infection and subsequent risk of HIV acquisition among both males and females. A subsequent meta-analysis that included 7 studies of HIV acquisition risk and cervical HPV infection noted an association between prevalent cervical HPV and HIV acquisition. In that meta-analysis, HIV acquisition risk among women doubled with prevalent HPV infection of any genotype (hazard ratio, 2.06; 95% CI, 1.44–2.94), although adjustment for confounders was often inadequate in studies that contributed data. The increased risk of HIV acquisition was similar for HR (hazard ratio, 1.99; 95% CI, 1.54–2.56) and LR HPV (hazard ratio, 2.01; 95% CI, 1.27–3.20).43
In some studies, clearance of HPV infection conferred an increased risk of HIV acquisition, whereas persistent infection with HPV did not increase the risk of acquiring HIV. In one investigation, loss of detection of any HPV DNA type among women was associated with HIV acquisition (odds ratio [OR], 5.4; 95% CI, 2.9–9.9).44 A prospective cohort study of Zimbabwean women found that nonpersistent HR (adjusted hazard ratio, 1.67; 95% CI, 1.03–2.70) and LR HPV infections (adjusted hazard ratio, 2.09; 95% CI, 1.27–3.44) were associated with increased risk of HIV acquisition.45 Among men, foreskin HPV clearance but not HPV acquisition of both HR (adjusted OR, 3.25; 95% CI, 1.11–9.55) and LR HPV (adjusted OR, 3.18; 95% CI, 1.14–8.90) was associated with HIV seroconversion.46 One study of men participating in a circumcision trial showed an association between HIV acquisition and prevalent HR but not LR urethral HPV infection.47
There is accumulating evidence to suggest that HPV clearance and regression of HPV-associated disease such as anogenital warts is preceded by a cell-mediated immune response with influx of immune cells. Observational studies have documented infiltration of CD4+ lymphocytes,48 and granzyme B–positive cells49 before lesion regression. In experimental models of mucosal papillomatosis, an influx of CD4+ and CD8+ lymphocytes precedes wart regression.50,51 In addition, anogenital warts are prone to bleeding and epithelial disruption. Taken together, one potential explanation for the association between HPV clearance and acquisition of HIV is that the influx of these HIV-susceptible immune cells into tissues that are friable and/or structurally altered due to HPV infection may put them at increased risk for exposure to HIV during sexual intercourse.52 Confirmation of the role of HPV infection in increasing the risk of HIV acquisition may require clinical trials demonstrating reduction in HIV rates in HPV-vaccinated cohorts when compared with those not vaccinated.53,54
In summary, an increasing number of reports point to higher incidence of cancers among individuals with a prior diagnosis of anogenital warts than those without. However, a direct role for LR HPV seems unlikely. In addition, HPV infection and development of associated lesions may potentiate HIV acquisition, although the relative contribution of LR and HR types is not yet known. Further investigation of mechanisms underlying HPV involvement, including possible contribution of LR HPV types, will provide knowledge on this important public health issue.
1. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Monograph on Human Papillomaviruses. Vol 90. Lyon, France: International Agency for Research on Cancer; 2007; 90: 1–179.
2. Bernard HU, Burk RD, Chen Z, et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010; 401: 70–79.
4. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: Addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009; 4: 8.
5. Castle PE. The evolving definition of carcinogenic human papillomavirus. Infect Agent Cancer 2009; 4: 7.
6. Srodon M, Stoler MH, Baber GB, et al. The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). Am J Surg Pathol 2006; 30: 1513–1518.
7. Hoots BE, Palefsky JM, Pimenta JM, et al. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer 2009; 124: 2375–2383.
8. D'Hauwers KW, Depuydt CE, Bogers JJ, et al. Human papillomavirus, lichen sclerosus and penile cancer: A study in Belgium. Vaccine 2012; 30: 6573–6577.
9. Clifford G, Franceschi S, Diaz M, et al. Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 2006; 24(suppl 3): S3/S26–S34.
10. Kim KM, Cho NH, Choi HS, et al. Effect of human papilloma virus expression on clinical course of laryngeal papilloma. Acta Otolaryngol 2008; 128: 1138–1144.
11. Makiyama K, Hirai R, Matsuzaki H, et al. Assessment of human papilloma virus infection in adult laryngeal papilloma using a screening test. J Voice 2013; 27: 230–235.
12. Hawkins MG, Winder DM, Ball SL, et al. Detection of specific HPV subtypes responsible for the pathogenesis of condylomata acuminata. Virol J 2013; 10: 137.
13. Lacey CJ, Lowndes CM, Shah KV. Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 2006; 24(suppl 3): S3/35–S3/41.
14. Garland SM, Steben M, Sings HL, et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis 2009; 199: 805–814.
15. Patel H, Wagner M, Singhal P, et al. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis 2013; 13: 39.
16. Raymakers AJ, Sadatsafavi M, Marra F, et al. Economic and humanistic burden of external genital warts. Pharmacoeconomics 2012; 30: 1–16.
17. Sherman KJ, Daling JR, Chu J, et al. Genital warts, other sexually transmitted diseases, and vulvar cancer. Epidemiology 1991; 2: 257–262.
18. Sigurgeirsson B, Lindelöf B, Eklund G. Condylomata acuminata and risk of cancer: An epidemiological study. BMJ 1991; 303: 341–344.
19. Friis S, Kjaer SK, Frisch M, et al. Cervical intraepithelial neoplasia, anogenital cancer, and other cancer types in women after hospitalization for condylomata acuminata. J Infect Dis 1997; 175: 743–748.
20. Sinha P, Logan HL, Mendenhall WM. Human papillomavirus, smoking, and head and neck cancer. Am J Otolaryngol 2012; 33: 130–136.
21. Castellsagué X, Muñoz N. Chapter 3: Cofactors in human papillomavirus carcinogenesis—Role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr 2003: 20–28.
22. Giuliano AR, Sedjo RL, Roe DJ, et al. Clearance of oncogenic human papillomavirus (HPV) infection: Effect of smoking (United States). Cancer Causes Control 2002; 13: 839–846.
23. Wei L, Gravitt PE, Song H, et al. Nitric oxide induces early viral transcription coincident with increased DNA damage and mutation rates in human papillomavirus–infected cells. Cancer Res 2009; 69: 4878–4884.
24. Wittekindt C, Wagner S, Mayer CS, et al. Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer. GMS Curr Top Otorhinolaryngol Head Neck Surg 2012; 11: Doc09.
25. Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata. Int J Cancer 2006; 119: 888–893.
26. Blomberg M, Friis S, Munk C, et al. Genital warts and risk of cancer: A Danish study of nearly 50 000 patients with genital warts. J Infect Dis 2012; 205: 1544–1553.
27. Kjaer SK, Dahl C, Engholm G, et al. Case-control study of risk factors for cervical neoplasia in Denmark. II. Role of sexual activity, reproductive factors, and venereal infections. Cancer Causes Control 1992; 3: 339–348.
28. Madsen BS, Jensen HL, van den Brule AJ, et al. Risk factors for invasive squamous cell carcinoma of the vulva and vagina—Population-based case-control study in Denmark. Int J Cancer 2008; 122: 2827–2834.
29. Madsen BS, van den Brule AJ, Jensen HL, et al. Risk factors for squamous cell carcinoma of the penis—Population-based case-control study in Denmark. Cancer Epidemiol Biomarkers Prev 2008; 17: 2683–2691.
30. Tseng HF, Morgenstern H, Mack T, et al. Risk factors for penile cancer: Results of a population-based case-control study in Los Angeles County (United States). Cancer Causes Control 2001; 12: 267–277.
31. Daling JR, Madeleine MM, Schwartz SM, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002; 84: 263–270.
32. del Pino M, Bleeker MC, Quint WG, et al. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma. Mod Pathol 2012; 25: 1354–1363.
33. Bergeron C, Ronco G, Reuschenbach M, et al. The clinical impact of using p16(INK4a) immunochemistry in cervical histopathology and cytology: An update of recent developments. Int J Cancer 2015; 136: 2741–2751.
34. Garret M. Relationship of podophyllin to carcinogenesis. A comparison of cytologic and histologic changes induced by podophyllin in the mouse cervix with those induced by 3,4 benzpyrene. Cancer 1966; 19: 947–958.
35. Kaminetzky HA, McGrew EA, Phillips RL. Experimental cervical epithelial dysplasia. Obstet Gynecol 1959; 14: 1–10.
36. Kaminetzky HA, McGrew EA. Podophyllin and mouse cervix. Effect of long-term application. Arch Pathol 1962; 73: 481–485.
37. Roe FJ, Salaman MH. Further studies on incomplete carcinogenesis: Triethylene melamine (T.E.M.), 1,2-benzanthracene and beta-propiolactone, as initiators of skin tumour formation in the mouse. Br J Cancer 1955; 9: 177–203.
38. Longstaff E, von Krogh G. Condyloma eradication: self-therapy with 0.15–0.5% podophyllotoxin versus 20–25% podophyllin preparations—An integrated safety assessment. Regul Toxicol Pharmacol 2001; 33: 117–137.
39. Taper HS. Induction of the deficient acid DNAse activity in mouse interfollicular epidermis by croton oil as a possible tumor promoting mechanism. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1977; 90: 197–210.
41. Anic GM, Lee JH, Stockwell H, et al. Incidence and human papillomavirus (HPV) type distribution of genital warts in a multinational cohort of men: The HPV in Men Study. J Infect Dis 2011; 204: 1886–1892.
42. van der Loeff MF, Nyitray AG, Giuliano AR. HPV vaccination to prevent HIV infection: time for randomized controlled trials. Sex Transm Dis 2011; 38: 640–643.
43. Houlihan CF, Larke N, Watson-Jones D, et al. HPV infection & increased risk of HIV acquisition. A systematic review & meta-analysis. Poster presentation at the XIX International AIDS Conference; July 22–27, 2012; Washington, DC. 2012.
44. Averbach SH, Gravitt PE, Nowak RG, et al. The association between cervical human papillomavirus infection and HIV acquisition among women in Zimbabwe. AIDS 2010; 24: 1035–1042.
45. Smith-McCune KK, Shiboski S, Chirenje MZ, et al. Type-specific cervico-vaginal human papillomavirus infection increases risk of HIV acquisition independent of other sexually transmitted infections. PLoS One 2010; 5: e10094.
46. Tobian AA, Grabowski MK, Kigozi G, et al. Human papillomavirus clearance among males is associated with HIV acquisition and increased dendritic cell density in the foreskin. J Infect Dis 2013; 207: 1713–1722.
47. Auvert B, Lissouba P, Cutler E, et al. Association of oncogenic and nononcogenic human papillomavirus with HIV incidence. J Acquir Immune Defic Syndr 2010; 53: 111–116.
48. Coleman N, Birley HD, Renton AM, et al. Immunological events in regressing genital warts. Am J Clin Pathol 1994; 102: 768–774.
49. Woo YL, Sterling J, Damay I, et al. Characterising the local immune responses in cervical intraepithelial neoplasia: A cross-sectional and longitudinal analysis. BJOG 2008; 115: 1616–1621.
50. Nicholls PK, Moore PF, Anderson DM, et al. Regression of canine oral papillomas is associated with infiltration of CD4+
lymphocytes. Virology 2001; 283: 31–39.
51. Handisurya A, Day PM, Thompson CD, et al. Strain-specific properties and T cells regulate the susceptibility to papilloma induction by Mus musculus
papillomavirus 1. PLoS Pathog 2014; 10: e1004314.
52. de Jong MA, Geijtenbeek TB. Human immunodeficiency virus-1 acquisition in genital mucosa: Langerhans cells as key-players. J Intern Med 2009; 265: 18–28.
53. Schim van der Loeff MF, Giuliano AR. Human papillomavirus vaccination: Component of an integrated HIV prevention program? AIDS 2012; 26: 2251–2252.
54. Lissouba P, Van de Perre P, Auvert B. Association of genital human papillomavirus infection with HIV acquisition: A systematic review and meta-analysis. Sex Transm Infect 2013; 89: 350–356.