Vaginal cancer - risk factors

Information on the risk factors for vaginal cancer is presented on this page. Human papillomavirus (HPV) infection is the primary risk factor for vaginal cancer. Other potential risk factors have been studied, including non-HPV sexually transmitted infections, exposure to diethylstilboestrol (DES) in the womb, and smoking. However as the number of vaginal cancer cases is low, evidence for most risk factors is sparse.

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Human papillomavirus

A 2009 meta-analysis of 93 studies found human papillomavirus (HPV) is present in more than two-thirds of invasive vaginal tumours.1 Pre-cancerous vaginal tumours are even more likely to be HPV-positive, with the virus found in around 90% of grade 2/3 vaginal intraepithelial neoplasia (VAIN) and in 100% of grade 1 VAIN.1 HPV16 is the most common type found in vaginal tumours (around 45% of VAIN cases and around 54% of invasive vaginal tumours are HPV16-positive),1 and although other HPV types are found, currently, the International Agency for Research on Cancer (IARC) does not classify any other HPV type apart from HPV16 as a cause of vaginal cancer.2

The presence of HPV16 antibodies increases the risk for invasive vaginal tumours by up to six times, and increases the risk of VAIN by 13 times.3,4 A doubling in risk has been reported for VAIN but not invasive tumours in women with HPV 18 seropositivity.3,4

HPV infection is also implicated in a number of other cancers and conditions, which in turn have been shown to have an association with vaginal cancer risk. Women with a previous cervical cancer or cervical intraepithelial neoplasia have an increased risk for vaginal cancer.5-9 Risk falls with time since diagnosis of cervical cancer, but remains higher than the general population for at least 25 years.7 Increased risks for vaginal cancer have also been reported for women diagnosed with cancers at other anogenital sites,10 or with a family history of anogenital cancer.4,11 Genital warts (associated with infection with HPV 6 and HPV 11) have been shown to increase risk for VAIN by almost six-fold,12 but the association with invasive tumours is less clear.4,13 Increased risk is also reported for individuals with a prior squamous cell carcinoma of the skin, which may be related to HPV infection.14

Vaccination against HPV with the quadrivalent vaccine (against types 6, 11, 16 and 18)* has been shown to reduce the incidence of VAIN in studies from the US. In general population samples (called intention to treat analyses) including women who may have been infected with HPV before they were vaccinated,* up to around 4 years after vaccination, the incidence of low-grade VAIN caused by one of the vaccine HPV types was reduced by 83%,15 and the incidence of high-grade VAIN was reduced by 71-79%.16,17 The effect of HPV vaccination on invasive vaginal cancer has not yet been demonstrated, due to the low number of cases of the disease.

 

* The UK HPV vaccination programme uses the bivalent vaccine against types 16 and 18. The programme targets girls aged 12-13 years, who are assumed not to be infected with HPV before or during the vaccination programme. Studies of uninfected females like this (called per-protocol analyses) show HPV vaccines are 100% effective in preventing low-grade and high-grade VAIN.15,17

section updated 30/04/12

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Other sexually transmitted infections and medical conditions

The presence of antibodies to the herpes simplex virus type 2 in blood samples is associated with an increased risk of vaginal cancer and high-grade VAIN, after HPV infection is controlled for.4

HIV-positive women appear to be at increased risk of vaginal cancer and pre-cancer, though the magnitude of the increase varies in published papers from around 7 (vulval and vaginal cancer combined) to 21 times higher.18,19 Some studies show a particularly strong relationship for women under 30 years old.20,21 However, IARC does not classify the evidence as sufficient for a link between HIV and vaginal cancer.2

Women with systemic lupus erythematosus have between a three- and nine-fold increased risk of vaginal and vulval cancers.22,23 This may be due to an increased risk of HPV infection in these patients, many of whom take immunosuppressant medication.23,24

A 23-fold risk increase for vulval/vaginal cancer has been shown for people who have received organ transplants.18

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Diethylstilboestrol (DES)

DES was used in the 1940s-60s to prevent miscarriage, and has been linked to risk of clear cell adenocarcinomas of the vagina in daughters of women who were treated with the drug. The risk increase is as great as 40-fold,25 and is highest for women whose mothers were exposed to DES in the first trimester of pregnancy.26

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Smoking

A recent case-control study reported that current smokers had double the risk of vaginal SCC of non-smokers,4 but this association remains uncertain.13,27,28

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References for vaginal cancer risk factors

  1. De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: A meta-analysis. International Journal of Cancer 2009;124(7):1626-36.
  2. Cogliano VJ, Baan R, Straif K, Grosse Y, Lauby-Secretan B, El Ghissassi F, et al. Preventable Exposures Associated With Human Cancers. Journal of the National Cancer Institute 2011;103(24):1827-39.
  3. Carter JJ, Madeleine MM, Shera K, Schwartz SM, Cushing-Haugen KL, Wipf GC, et al. Human Papillomavirus 16 and 18 L1 Serology Compared across Anogenital Cancer Sites. Cancer Research 2001;61(5):1934-40.
  4. Daling JR, Madeleine MM, Schwartz SM, Shera KA, Carter JJ, McKnight B, et al. A Population-Based Study of Squamous Cell Vaginal Cancer: HPV and Cofactors. Gynecologic Oncology 2002;84(2):263-70.
  5. Evans HS, Newnham A, Hodgson SV, Møller H. Second primary cancers after cervical intraepithelial neoplasia III and invasive cervical cancer in Southeast England. Gynecologic Oncology 2003;90(1):131-36.
  6. Viikki M, Pukkala E, Hakama M. Risk of endometrial, ovarian, vulvar, and vaginal cancers after a positive cervical cytology followed by negative histology. Obstet Gynecol 1998;92(2):269-73.
  7. Strander B, Andersson-Ellström A, Milsom I, Sparén P. Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study. BMJ 2007;335(7629):1077.
  8. Edgren G, Sparén P. Risk of anogenital cancer after diagnosis of cervical intraepithelial neoplasia: a prospective population-based study. The Lancet Oncology 2007;8(4):311-16.
  9. Kalliala I, Anttila A, Pukkala E, Nieminen P. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study. BMJ 2005;331(7526):1183-85.
  10. Frisch M, Olsen JH, Melbye M. Malignancies that occur before and after anal cancer: clues to their etiology. Am J Epidemiol 1994;140(1):12-9.
  11. Hussain SK, Sundquist J, Hemminki K. Familial clustering of cancer at human papillomavirus-associated sites according to the Swedish Family-Cancer Database. International Journal of Cancer 2008;122(8):1873-78.
  12. Blomberg M, Friis S, Munk C, Bautz A, Kjaer SK. Genital warts and risk of cancer – a Danish study of nearly 50,000 patients with genital warts. Journal of Infectious Diseases 2012.
  13. Madsen BS, Jensen HL, van den Brule AJC, Wohlfahrt J, Frisch M. Risk factors for invasive squamous cell carcinoma of the vulva and vagina—Population-based case–control study in Denmark. International Journal of Cancer 2008;122(12):2827-34.
  14. Wassberg C, Thörn M, Yuen J, Ringborg U, Hakulinen T. Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden. International Journal of Cancer 1999;80(4):511-15.
  15. FUTURE I/II Study Group Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-Avila M, Perez G, Brown DR, Koutsky LA, Tay EH, García P, Ault KA, Garland SM, Leodolter S, Olsson SE, Tang GW, Ferris DG, Paavonen J, Lehtinen M, Steben M, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ 2010;341.
  16. Muñoz N, Kjaer SK, Sigurdsson K, Iversen O-E, Hernandez-Avila M, Wheeler CM, et al. Impact of Human Papillomavirus (HPV)-6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women. Journal of the National Cancer Institute 2010;102(5):325-39.
  17. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. The Lancet;369(9574):1693-702.
  18. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007;370(9581):59-67.
  19. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al. Incidence of Types of Cancer among HIV-Infected Persons Compared with the General Population in the United States, 1992–2003. Annals of Internal Medicine 2008;148(10):728-36.
  20. Frisch M, Biggar RJ, Goedert JJ. Human Papillomavirus-Associated Cancers in Patients With Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome. Journal of the National Cancer Institute 2000;92(18):1500-10.
  21. Sitas F, Pacella-Norman R, Carrara H, Patel M, Ruff P, Sur R, et al. The spectrum of HIV-1 related cancers in South Africa. International Journal of Cancer 2000;88(3):489-92.
  22. Parikh-Patel A, White R, Allen M, Cress R. Cancer risk in a cohort of patients with systemic lupus erythematosus (SLE) in California. Cancer Causes and Control 2008;19(8):887-94.
  23. Dreyer L, Faurschou M, Mogensen M, Jacobsen S. High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: A long-term followup study in a Danish cohort. Arthritis Rheumatism 2011;63(10):3032-37.
  24. Klumb EM, Pinto AC, Jesus GR, Araujo M, Jr., Jascone L, Gayer CR, et al. Are women with lupus at higher risk of HPV infection? Lupus 2010;19(13):1485-91.
  25. Hatch EE, Palmer JR, Titus-Ernstoff L, Noller KL, Kaufman RH, Mittendorf R, et al. Cancer Risk in Women Exposed to Diethylstilbestrol In Utero. JAMA: The Journal of the American Medical Association 1998;280(7):630-34.
  26. Herbst AL, Anderson S, Hubby MM, Haenszel WM, Kaufman RH, Noller KL. Risk factors for the development of diethylstilbestrol-associated clear cell adenocarcinoma: a case-control study. Am J Obstet Gynecol 1986;154(4):814-22.
  27. Brinton LA, Nasca PC, Mallin K, Schairer C, Rosenthal J, Rothenberg R, et al. Case-control study of in situ and invasive carcinoma of the vagina. Gynecologic Oncology 1990;38(1):49-54.
  28. Daling JR, Sherman KJ, Hislop TG, Maden C, Mandelson MT, Beckmann AM, et al. Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol 1992;135(2):180-9.