Medical Education Library

Update on human papillomavirus



Cervical cancer is the most common cancer caused by the human papillomavirus (HPV),1 but the scope of HPV-related disease is considerably broader. As many as 90% of anal cancers, as well as 40% of vulvar and penile cancers, are attributable to HPV infection.2 Furthermore, high-risk HPV types contribute significantly to cases of vulvar and vaginal disease3 and low-risk types of HPV are thought to cause up to 1 million cases of genital warts each year.4 Vaccination has been shown to be highly effective in preventing HPV infection5 and its sequelae.6

Some of these findings were presented in detail on November 10, 2008, by 3 experts at a symposium supported by an independent educational grant from Merck & Co., Inc., at the American Society for Reproductive Medicine 64th Annual Meeting in San Francisco. These clinicians also presented promising results showing cross-protection against several HPV types; provided tips to improve detection of vaginal lesions; and discussed the implications of gender-neutral vaccination. Following are short synopses of each physician’s presentation.

Epidemiology and natural history of HPV in benign and malignant disease: Primary prevention of CIN3 and AIS with HPV vaccination


Most sexually active women will acquire HPV in their lifetime.7 Although the infection clears in most cases, it does persist in some women. Long-term persistence of HPV infection—particularly with high-risk types—has been established as a necessary cause of precancerous lesions.8 In fact, the high-risk HPV types 16 and 18 are responsible for 70% of squamous cell carcinoma cases and 86% of cases of adenocarcinoma.9

Persistent HPV infection and cervical intraepithelial neoplasia 3 (CIN 3) allow random mutations to accumulate that can eventually lead to cancer. When mutations occur in normal cells, the cell upregulates the expression of proteins that repair the mutation or precipitate apoptosis. High-risk types of the HPV virus produce proteins that inhibit this process, allowing cells to live despite mutations. In the worst case, these cells continue to grow and mutate, forming a malignancy over many years that invades the basement membrane.

Prophylactic administration of the HPV vaccine effectively prevents the development of CIN 1, 2, 3, and adenocarcinoma in situ (AIS). In patients who tested negative for the vaccine HPV types during the administration of the 3-dose vaccine, protection against high-grade cervical lesions (CIN 2 and 3) and AIS was between 97% and 100% at 3 years.6,10 Vaccination was also effective in eliminating the development of genital warts and CIN 1, which are caused by low-risk HPV types 6 and 11.6

Additionally, vaccination appears to offer cross-protection, ie, partial protection against infection with HPV types related to 16 or 18, such as the high-risk types 45, 31, 33, and 52.11

Update on HPV: Genital warts, VIN, VAIN, and vulvar/vaginal cancer


Vulvo-vaginal disease and genital warts can be sequelae of HPV infection. Genital warts represent a large burden: Treatment costs account for nearly one-third of annual medical expenses for sexually transmitted infections.12 And vulvar intraepithelial neoplasia (VIN) is a growing burden. Although the incidence of VIN remains low, rates of diagnosis of VIN 2 and 3 are increasing.13 This is particularly troubling, given that 10% of untreated VIN 3 progresses to cancer.14 Further, VIN may not be diagnosed until it has progressed, because only subjective diagnostic criteria exist for low-grade VIN.15

Visual inspection is used to identify genital warts and vulvar or vaginal lesions. Vulvar or vaginal lesions are more difficult to detect with colposcopy than are cervical lesions, due to the wider target area and tangential angle of viewing. Applying a solution of 5% acetic acid and leaving it for 3 to 5 minutes will facilitate evaluation; small vaginal lesions are best detected with Lugol’s solution.

A bimanual examination that includes palpation of the vagina should be conducted in order to rule out invasive cancer.

HPV types 6 and 11 cause 90% of genital warts.16 High-risk HPV types 16 and 18 are responsible for many cases of vaginal and vulvar disease3:

• 76% of VIN 2/3
• 64% of vaginal intraepithelial neoplasia (VAIN) 2/3
• 42% of vulvar cancer

A meta-analysis of 3 randomized controlled trials evaluated the development of vulvar or vaginal lesions with prophylactic administration of the HPV vaccine.17 Among women who were HPV negative before and during administration of the HPV vaccine, the vaccine was 100% effective in preventing VIN 2/3 and VAIN 2/3 related to either HPV 16 or 18. The incidence of VIN 2/3 and VAIN 2/3 decreased by 71% among women who had previously been exposed to HPV.


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