Human Papillomavirus: A Brief Review Beyond Cervical Cancer
Jessica Moore, ND, FABNO
Over 15% of human cancers can be attributed to infectious agents, and current research suggests that 1/3 to 1/2 of these cases may be due to infection by human papillomaviruses (HPVs). This group is composed of over 150 related double-stranded DNA viruses. They are transmitted through skin-to-skin or skin-to-mucosa contact.1,2 As the most common sexually transmitted infection, HPVs confer at least an 80% risk of mucocutaneous infection by age 50.3 HPV types 6 and 11 rarely lead to cancers (ie, laryngeal cancer), but are responsible for over 90% of genital warts.4 Among the oncogenic strains, types 16 and 18 are associated with the majority (~70%) of HPV-related cancer cases worldwide.5 In most cases, infections are transient and cleared by the host within 6 to 24 months; however, 500 000 to 1 million new cases of genital warts, and approximately 13 170 new cases of invasive cervical cancer, are diagnosed annually in the United States alone.6
Beyond what is well characterized with regard to cervical cancer, HPV is associated with cancers of the oropharynx, oral cavity, tonsil, anus, vulva, vagina, and penis.7 Ongoing research is also assessing potential pathogenetic links between HPV and lung cancer, breast cancer, prostate cancer, skin cancers, glioblastoma multiforme (GBM), ovarian cancer, neoplasms of the pancreas, carcinoma of the urinary bladder, cancer of the conjunctiva, and other malignant tumors.8-16 In some tumor types, HPV may also affect prognostic outcomes or influence the selection of systemic therapies.17 Lastly, HPV infection has also been implicated in other conditions, such as systemic lupus erythematosus (SLE) and male infertility.18,19
The impact of HPVs on human health may be more substantial than previously thought. Research is preliminary in many areas of HPV-related pathology. Clinicians should be familiar with HPV risk factors and stay up to date on ongoing research. The intent of this of this brief review is to discuss the foundational oncogenic pathophysiology of HPVs, briefly mention the non-cervical cancers with which HPV may be associated, and review potential modifiable risk factors that clinicians may consider. Please note that while it is important that practitioners be well informed on HPV vaccination guidelines, they are outside of the focus of this review and will not be discussed within this text.
Oncogenic Pathophysiology of HPVs
Low risk genotypes, such as HPV 6 & 11, can cause benign anogenital warts and papillomas.3
High risk genotypes: HPV 16 is the most prevalent type detected in HPV-associated cancers, followed by HPV 18.3
The difference in ability of HPVs to promote malignant transformation determines their classification into low- and high-risk types. Only a subset of HPVs has demonstrated causation in human cancers. The International Agency for Research on Cancer declared 12 HPVs carcinogenic (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59).20 The carcinogenicity of HPV 16 is well recognized. It persists longer than other carcinogenic genotypes, thereby increasing the chance of malignant transformation. HPVs are regarded as an exclusive epitheliotropic pathogen. They infect mucosal and cutaneous squamous epithelial tissues, with a preference for squamous-cell columnar cell junctions. The initial infection occurs in the basal layer of the epithelium following microtrauma that exposes the epithelial basement membrane and basal cells. After a microtrauma, these cells likely assume a stem cell phenotype during the wound healing process (wound keratinocytes). The virus infects the wound keratinocytes in their susceptible state, and then the virus and cell replicate together as the cell proliferates and differentiates. Because there is no viremia, virus-induced cell death, or inflammation, there is no danger signal for the immune system to act upon. Eventually, viral proteins, detectable by the immune system, are produced at sufficient levels in the suprabasal cells, but this is in the later stages of HPV infection. HPV quietly downregulates the innate immune system and suppresses type I interferon.1-3,21
While all HPVs encode replicative and capsid proteins (E1, E2, E3, E4), the carcinogenic HPVs also encode accessory proteins: E4, E5, E6 and E7.1 These accessory proteins are used to manipulate the cellular environment to enhance viral replication. Of particular importance is the expression of E6 and E7 proteins. Both directly inhibit innate immune responses, as well as delay adaptive immune responses. E6 also degrades tumor suppressor gene p53 and PDZ, while upregulating telomerases.1 E7 degrades another important tumor suppressor, retinoblastoma protein (pRb). These changes along, with several others, lead to cell cycle dysregulation, the accumulation of cellular genome mutations required for malignant conversion, suppression of apoptotic processes, cell immortalization, and uncontrolled cell division.1,2
p53 is a critical cellular gatekeeper responsible for inducing apoptosis, cell-cycle arrest, senescence, or modulation of autophagy. It is activated in response to cell stressors such as DNA damage, oncogene activation, or hypoxia. Loss of p53 is seen in over 50% of all cancers.22
PDZ binding domain proteins are normally involved in cellular homeostasis (signal transduction pathways, immune cell recognition, cell proliferation, migration, invasion, attachment, and apoptosis).23
pRb is normally a major G1 checkpoint, blocking S-phase entry and regulating control of the cell cycle.24
Clinical and physiological concepts to keep in perspective include the following: 1) 90% of HPV infections are cleared by the host within 6-24 months; 2) only the persistence of HPV can cause progression to malignant disease; 3) malignant potential is also likely dependent on in the presence of appropriate risk factors, activators, and synergistic factors (eg, smoking history, medical conditions, immunocompromised status, co-infections, etc); and 4) not all strains are oncogenic.2,3,5
Non-cervical HPV-associated Malignancies
Given that basal cell epithelium is found in many tissues and that host-to-host transmission is highly prevalent, it is not surprising that HPV might infect issues other than the cervix. However, readers should be aware that the data on many non-cervical HPV-attributable cancers are often conflicting and that the research is in its early phases of assessment. Variation among studies is observed by study method and geographic region.10
While HPV detection rates across lung cancer research studies are variable (ranging from 0-100%), a 2017 meta-analysis of 37 studies, including lung cancer cases and control patients, concluded that HPV 16 and 18 may confer an increased risk for lung cancer. Infection was associated not only with squamous cell carcinoma, but (surprisingly) also adenocarcinoma and small cell carcinoma.8 Other studies have suggested interesting associations such as higher risks for lung cancer in patients with HPV-associated anogenital cancers.25,26
Although the association between HPV infections and the risk of breast or prostate cancer remains inconclusive, studies have demonstrated the presence of high-risk HPV or the expression of HPV viral proteins in malignant breast or prostate tissue. A recent 2019 study examining 72 breast cancer patients and 31 healthy controls found HPV DNA in 48.6% of breast cancer tissue specimens vs only 16.1% of controls.9 This was statistically significant. The presence of HPV was also associated with an increase in inflammatory cytokines and tumor progression.9 Similarly, a 2015 meta-analysis of 26 prostate tissue-based case-control studies suggested a significantly increased risk of prostate cancer in prostate HPV-positive specimens.10
In non-cervical cancers, malignancy-associated HPV infection can confer either a positive or negative prognostic effect, depending on the tissue and the viral type. HPV is linked to approximately 20-72% of oropharyngeal cancers.27 HPV-positive oropharyngeal cancers are highly susceptible to radiation and anticancer drugs and are generally associated with improved overall and disease-free survival compared with HPV-negative oropharyngeal cancer.27 As such, P16 immunostaining or HPV testing is recommended prior to classifying the tumor and for definitive treatment planning. The 8th edition of the AJCC/UICC staging system for HPV-associated oropharyngeal squamous cell carcinoma accounts for this improved survival outcome over HPV-negative cancers.28 This difference may be due to multiple factors, possibly including: fewer or different genetic alterations, maintenance of an apoptotic response to radiation therapy, immune stimulation from viral antigens, a younger age in HPV+ patients, or others.
p16 overexpression is a surrogate biomarker of HPV infection, especially in head and neck cancers.27,28
Conversely, a 2014 study analyzed 52 primary human glioblastoma specimens retrospectively for the presence of HPV, and observed a worse prognosis when HPV was identified.12 The authors of this single study concluded that HPV might be an independent prognostic risk factor and should be recognized as a causative agent in gliomagenesis. As previously mentioned, HPV has demonstrated a tropism for epithelial tissues; therefore, the access of HPV to GBM clearly requires further consideration. This is an example of how these early and inconclusive investigations challenge the classic oncogenesis model, as discussed above, and require further investigation.
Modifiable Risk Factors & Natural Agents
It is likely that a combination of traditional risk factors, family history, lifestyle habits, environmental exposures, and/or co-infections are required for HPV to manifest in malignancy, as opposed to high-risk HPV strains acting as a sole causative agent. Clinicians may wish to consider the following on a case-by-case basis:
- Sexual partners: Higher numbers of sexual partners is associated with HPV infection in both women and men. A 2007 case-controlled study, published in the New England Journal of Medicine,investigated an association between HPV and oropharyngeal squamous cell carcinoma. Findings revealed an increased risk in patients with 26 or more vaginal-sex partners or with 6 or more oral-sex partners, independent of tobacco and alcohol use.29
- Condoms: The use of condoms may decrease the risk of HPV transmission.30,31
- Co-infection: HIV predisposes to higher rates and risk of HPV-related cancer due to progressive immune suppression.32 Co-infections with other pathogens, such as Epstein-Barr virus,33 herpes simplex virus type 2,34 or Chlamydia,35 may also be synergistic with HPV. Studies have produced conflicting results.33,36,37
- Microflora instability: Microflora imbalances in the form of vaginal yeast infections or bacterial vaginosis (BV) may be linked to persistence of cervical HPV infections. Some clinicians elect to treat asymptomatic BV in women with cervical HPV infections.38,39 Although there is no clear link between the oral or pharyngeal microbiome and HPV, some studies have suggested a possible link between chronic periodontitis and HPV infection.40 A 2017 study, published in the journal Cancer, concluded that routine dental visits may cut the risk for both HPV-positive or -negative oropharyngeal carcinoma nearly in half.41
- Smoking: Tobacco smoking poses an additional risk for the development of head and neck cancer. As in cervical cancer cases, a synergistic effect of smoking is seen in the setting of HPV progression from infection to dysplasia and then invasive carcinoma,42 although this link is not as clearly understood in non-cervical carcinoma. Conversely, some studies suggest smoking may be more associated with non-HPV-related carcinomas.41
- Partner viral load: Evidence among heterosexual couples suggests that a partner’s HPV viral load is associated with transmission and new detection of HPV infections. Some studies have shown an association between HPV-related carcinoma and HPV-positive cervical dysplasia in partners.43 There is a need for interventions to reduce partner viral load and transmission.
- Nutrients/Diet: Ongoing research is assessing the potential link between nutrient deficiencies and HPV infection or persistence of it. Data for non-cervical infection are lacking. Research into cervical-related HPV has demonstrated that circulating vitamin B12 levels may be inversely associated with oncogenic HPV persistence.44 One interesting study of Brazilian women suggested lutein/zeaxanthin, β-cryptoxanthin, and vitamin C intake may also be associated with reduced persistence of HPV infection, as was consumption of papaya >1 time per week.45
- Natural medicines: Recent early studies have demonstrated durable clearance of HPV in vitro and in vivo using activated hexose correlated compound (AHCC).46 AHCC is a standardized extract of cultured Lentinula edodes Confirmatory studies are underway.46
Since HPV is a sexually transmitted disease with a risk for re-infection, HPV-status of the patient’s sexual partner warrants further investigation in future research. With such investigation, perhaps therapies such as AHCC may be considered for both the patient and his/her sexual partner.14 AHCC may be a strong candidate to aid in this effort.
The role of HPVs in non-cervical cancer is currently poorly understood relative to the potential applications and implications. However, research in this area holds the possibility for prognostic- and treatment-defined changes to oncology care. Further investigation is warranted.
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- Bodily J, Laimins LA. Persistence of human papillomavirus infections: keys to malignant progression. Trends Microbiol. 2011;19(1):33-39.
- Smith M. HPV Related Cancers: Tip of a Very Large Iceberg. October 2017. The University of British Columbia Faculty of Medicine. Available at: https://ubcmj.med.ubc.ca/hpv-related-cancers-tip-of-a-very-large-iceberg/. Accessed July 2, 2019.
- Gissmann LL, Wolnik L, Ikenberg H, et al. Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci U S A. 1983;80(2):560-563.
- Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16(1):1-17.
- Yanofsky VR, Patel RV, Goldenberg G. Genital warts: a comprehensive review. J Clin Aesthet Dermatol. 2012;5(6):25-36.
- Chaturvedi AK. Beyond cervical cancer: burden of other HPV-related cancers among men and women. J Adolesc Health. 2010;46(4 Suppl):S20-S26.
- Xiong WM, Xu QP, Li X, et al. The association between human papillomavirus infection and lung cancer: a system review and meta-analysis. Oncotarget. 2017;8(56):96419-96432.
- Khodabandehlou N, Mostafaei S, Etemadi A, et al. Human papilloma virus and breast cancer: the role of inflammation and viral expressed proteins. BMC Cancer. 2019;19(1):61.
- Yin B, Liu W, Yu P, et al. Association between human papillomavirus and prostate cancer: A meta-analysis. Oncol Lett. 2017;14(2):1855-1865.
- Dréau D, Culberson C, Wyatt S, Holder WD Jr. Human papilloma virus in melanoma biopsy specimens and its relation to melanoma progression. Ann Surg. 2000;231(5):664-671.
- Vidone M, Alessandrini F, Marucci G, et al. Evidence of association of human papillomavirus with prognosis worsening in glioblastoma multiforme. Neuro Oncol. 2014;16(2):298-302.
- Zhang PP, Zhou L, Cao JS, et al. Possible Epithelial Ovarian Cancer Association with HPV18 or HPV33 Infection. Asian Pac J Cancer Prev. 2016;17(6):2959-2964.
- Tong TR, Chan A, Lai TW, et al. Identification of HPV-16 in Borderline Mucinous Cystic Neoplasm of Pancreas. Int J Biomed Sci. 2007;3(1):72-75.
- Barghi MR, Rahjoo T, Borghei M, et al. Association between the evidence of human papilloma virus infection in bladder transitional cell carcinoma in men and cervical dysplasia in their spouses. Arch Iran Med. 2012;15(9):572-574.
- Ateenyi-Agaba C, Franceschi S, Wabwire-Mangen F, et al. Human papillomavirus infection and squamous cell carcinoma of the conjunctiva. Br J Cancer. 2010;102(2):262-267.
- Mehta V, Moore-Medlin T, Flores JM, et al. Survival outcomes based on systemic agent used concurrently with radiation in human-papillomavirus associated oropharyngeal cancer. Oncotarget. 2017;8(41):70907-70915.
- Shi LH, Huang JY, Liu YZ, et al. Risk of systemic lupus erythematosus in patients with human papillomavirus infection: a population-based retrospective cohort study. Lupus. 2018;27(14):2279-2283.
- Lyu Z, Feng X, Li N, et al. Human papillomavirus in semen and the risk for male infertility: a systematic review and meta-analysis. BMC Infect Dis. 2017;17(1):714.
- Gargano J, Meites E, Watson M, et al. Chapter 5: Human Papillomavirus (HPV). Last reviewed November 10, 2017. CDC Web site. https://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.html. Accessed July 2, 2019.
- Stanley MA. Epithelial Cell Responses to Infection with Human Papillomavirus. Clin Microbiol Rev. 2012;25(2):215-222.
- Zilfou JT, Lowe SW. Tumor suppressive functions of p53. Cold Spring Harb Perspect Biol. 2009;1(5):a001883.
- Nagasaka K, Kawana K, Osuga Y, Fujii T. PDZ domains and viral infection: versatile potentials of HPV-PDZ interactions in relation to malignancy. Biomed Res Int. 2013;2013:369712.
- Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25(38):5220-5227.
- Lin FC, Huang JY, Tsai SC, et al. The association between human papillomavirus infection and female lung cancer: A population-based cohort study. Medicine (Baltimore). 2016;95(23):e3856.
- Frisch M, Melbye M. Risk of lung cancer in pre- and post-menopausal women with ano-genital malignancies. Int J Cancer. 1995;62(5):508-511.
- Elrefaey S, Massaro MA, Chiocca S, et al. HPV in oropharyngeal cancer: the basics to know in clinical practice. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.
- AJCC Cancer Staging Form Supplement. AJCC Cancer Staging Manual, Eighth Edition. Last updated June 5, 2018. Available at: https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC%20Cancer%20Staging%20Form%20Supplement.pdf. Accessed July 2, 2019.
- D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944-1956.
- Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006;354(25):2645-2654.
- Hariri S, Warner L. Condom use and human papillomavirus in men. J Infect Dis. 2013;208(3):367-369.
- Liu G, Sharma M, Tan N, Barnabas RV. HIV-positive women have higher risk of human papilloma virus infection, precancerous lesions, and cervical cancer. AIDS. 2018;32(6):795-808.
- Moore-Medlin T, Asarkar A, Ma X, et al. The Role of Human Papillomavirus and Epstein-Barr Virus Co-infection in Oropharyngeal Squamous Cell Tumor Differentiation. Int J Radiat Oncol. 2018;100(5):1352-1353.
- Smith JS, Herrero R, Bosetti C, et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst. 2002;94(21):1604-1613.
- Nonato DR, Alves RR, Ribeiro AA, et al. Prevalence and factors associated with coinfection of human papillomavirus and Chlamydia trachomatis in adolescents and young women. Am J Obstet Gynecol. 2016;215(6):753.e1-753.e9.
- Gupta P, Haldar D, Naru J, et al. Prevalence of human papillomavirus, Epstein-Barr virus, and cytomegalovirus in fine needle aspirates from lung carcinoma: A case-control study with review of literature. Diagn Cytopathol. 2016;44(12):987-993.
- Guidry JT, Myers JE, Bienkowska-Haba M, et al. Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes. J Virol. 2019;93(2). pii: e01216-18. doi: 10.1128/JVI.01216-18.
- Kero K, Rautava J, Syrjänen K, et al. Association of asymptomatic bacterial vaginosis with persistence of female genital human papillomavirus infection. Eur J Clin Microbiol Infect Dis. 2017;36(11):2215-2219.
- de Castro-Sobrinho MJ, Rabelo-Santos HS, Fugueiredo-Alves RR, et al. Bacterial vaginosis and inflammatory response showed association with severity of cervical neoplasia in HPV-positive women. Diagn Cytopathol. 2017;45(5):474-476.
- Tezal M, Sullivan Nasca M, Stoler DL, et al. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg. 2009;135(4):391-396.
- Mazul AL, Taylor JM, Divaris K, et al. Oral health and HPV-associated head and neck squamous cell carcinoma. Cancer. 2017;123(1):71-80.
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- Grabowski MK, Kong X, Gray RH, et al. Partner Human Papillomavirus Viral Load and Incident Human Papillomavirus Detection in Heterosexual Couples. J Infect Dis. 2016;213(6):948-956.
- Sedjo RL, Inserra P, Abrahamsen M, et al. Human papillomavirus persistence and nutrients involved in the methylation pathway among a cohort of young women. Cancer Epidemiol Biomarkers Prev. 2002;11(4):353-359.
- Giuliano AR, Siegel EM, Roe DJ, et al. Dietary intake and risk of persistent human papillomavirus (HPV) infection: the Ludwig-McGill HPV Natural History Study. J Infect Dis. 2003;188(10):1508-1516.
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Jessica Moore, ND, FABNO, is one of the few hospital and residency-trained naturopathic doctors in Canada. Dr Moore graduated in 2013 from the Southwest College of Naturopathic Medicine and completed a highly competitive cancer-focused 2-year hospital-based residency at Cancer Treatment Centers of America. After more than 2 additional years of practice as a hospital staff ND, she has transitioned to a private practice in Vancouver, BC. Dr Moore is a published author, public educator, and adjunct clinical faculty member at Boucher Institute of Naturopathic Medicine. You can contact Dr Moore at her practice locations: http://www.sageclinic.com and https://cancercare.tandemclinic.com.