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1. HPV is the most common sexually transmitted infection, resulting in ~14 million new infections annually in the U.S. Although there are an estimated 79 million HPV infections currently in the U.S., about 90% are asymptomatic and resolve within 2 to 3 years with no associated morbidity. The peak prevalence for HPV infections is seen in sexually active individuals 15 to 24 years old; this group represents 50% of all new HPV and other sexually transmitted infections. For this reason, it is not recommended that women under 30 years of age be routinely tested for HPV. In this patient population, HPV infection is most commonly transient and poses no risk for the development of cancer.

2. There are over 150 types of HPV, 40 of which can be sexually transmitted. HPV can cause either a cutaneous or mucosal infection depending on the tropism of the specific virus. Cutaneous infections present as non-genital warts, which include common warts, plantar warts, and flat warts. HPV types 1, 2, 3, 7, and 10 are most commonly associated with cutaneous warts. Although relatively common in all age groups, warts occur with a peak incidence in children aged 12 to 16. Mucosal infections include genital warts; cancers of the cervix, anus, external genitalia, and oropharnyx; and recurrent respiratory papillomatosis. Among sexually active individuals, genital warts range in prevalence from 1 to 10% with a peak incidence in 20- to 24-year-old persons. Risk factors associated with genital warts include infection with HPV types 6 and 11, introduction of new sexual partners, and an increased number of sexual partners. Cervical cancer is most commonly caused by persistent infection with types 16 and 18, which, combined, cause ~70% of cervical cancers. The remainder is caused by other high-risk HPV types. (See question 3 for further discussion of HPV and cervical cancer.) The incidence of HPV-associated anal cancer has been on the rise during the past 30 years and is primarily due to type 16. Risk factors for this uncommon cancer include female gender, HPV infection, increased number of partners, genital warts, cigarette smoking, receptive anal intercourse, and HIV infection. Some cancers of the external genitalia (penile, vulvar, and vaginal cancers) are associated with HPV infections and tend to occur in younger patients than HPV-negative cancers. Squamous cell carcinomas of the head and neck may also be due to HPV, but like cancers of the external genitalia, not all are associated with HPV. HPV-associated head and neck cancers are primarily found in the oropharynx and the base of the tongue and tonsil. Oral cancers due to HPV infection occur in younger individuals with increased sexual risk factors and are more common in men. Lastly, recurrent respiratory papillomatosis (RRP) is thought to be due to HPV acquisition during birth and presents as laryngeal warts in childhood, although adult cases have also been reported. RRP is associated with HPV types 6 and 11 and is generally benign. However, if not removed, laryngeal warts can lead to obstruction and can occasionally be aggressive and malignant.

3. The development of cervical cancer usually takes several years of persistent HPV infection. Thus, the patient’s recent change in sexual partners is likely not the initial source of the HPV infection causing her cervical changes. Disease progression is linked to high-risk oncogenic HPV types (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 69, 82), whereas low-risk types are only rarely associated with the development of cervical cancer and, therefore, are not routinely detected by HPV tests (e.g., 6, 11, 40, 42, 43, 44, 54, 61, 72, 81). Two main classification systems exist to describe HPV-associated changes in the cervical epithelium. The Bethesda system is primarily used to described changes seen by cytology (i.e., liquid-based Pap testing), whereas the CIN system is primarily used to describe the neoplasia seen by histology (i.e., biopsies obtained during colposcopy). Table 6.1 summarizes dysplasia classification and the associated interpretations. It should be noted that persistent HPV infection with a high-risk type most often does not progress through all of these stages. All precancerous stages have a significant likelihood of regression, with a greater percentage of the low-grade abnormalities regressing compared to high-grade dysplasia. It has been reported that up to 43% of CIN 2 and 32% of CIN 3 may regress without intervention. Invasive cancer is more commonly diagnosed in women over 40 years old, typically 8 to 13 years after identification of a high-grade lesion.

4. There are currently four FDA-approved tests for the detection of HPV DNA from liquid cytology specimens. The detection chemistries range from hybrid capture and Invader chemistry (signal amplification) to PCR and transcription-mediated amplification (target amplification of DNA and RNA, respectively). The initial clinical trials were performed with the hybrid capture system. Using CIN 2 or greater as an endpoint, hybrid capture had a 96% sensitivity (compared to 55% sensitivity of Pap smear). The development of amplification-based tests has led to an increase in analytic sensitivity, but no apparent increase in clinical sensitivity. The detection of HPV DNA by molecular screening has reduced cervical cancer rates by providing detection often prior to traditional cytology. Further, a negative HPV test in the setting of ASC-US prevents many unnecessary colposcopies. An additional advantage is the ability to detect only high-risk HPV types, which increases the clinical specificity of HPV detection. The more recently approved tests also have the ability to provide type-level results for types 16 and 18 such that positive women (even with normal Pap smear) will be followed by colposcopy due to the increased oncogenic potential of these types. One concern with the molecular methods is sample contamination, particularly if liquid cytology specimens are processed via automation. Some versions of automated processors have been shown to cross-contaminate specimens, but more recent automation appears not to have that problem. Nonetheless, to minimize the possibility of laboratory contamination, it is prudent to aliquot from the liquid cytology vial for HPV testing prior to placing the vial on an automated processor. Another concern is that a negative HPV test in a low-risk patient increases the time until the next Pap/HPV test to 5 years. Many physicians are concerned that patients will cease to present for annual health maintenance, which includes screens for many other important women’s health issues, such as breast cancer.

5. Three guidelines exist for cervical cancer screening. Guidelines updated in 2012 are available from the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP); from the American College of Obstetricians and Gynecologists (ACOG); and from the U.S. Preventative Services Task Force (USPSTF). All three guidelines agree that women younger than 21 years of age should not be screened by any method and that women 21 to 29 years of age should be screened by cytology alone every 3 years. For women 30 to 65 years of age, it is recommended that co-testing by cytology and HPV molecular detection occur every 5 years. In addition, the ACS/ASCCP/ASCP guidelines state that primary HPV testing in the absence of cytology for women 30 to 65 years old is not recommended. Screening can be discontinued in posthysterectomy patients and after 65 years of age if the woman has a history of adequate screening. Screening should take place as above, independent of the woman’s vaccination status. These recommendations do not apply to women who have been diagnosed with a high-grade dysplasia or cervical cancer, are immunocompromised, or were exposed to diethylstilbestrol in utero, who need more frequent screening. Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used in the U.S. from 1938 to 1971 to prevent miscarriage and other pregnancy complications and has been shown to be associated with increased reproductive cancers.

TABLE 6.1 THE BETHESDA CLASSIFICATION SYSTEM FOR CERVICAL SQUAMOUS CELL DYSPLASIAa

BETHESDA SYSTEM 1999	BETHESDA SYSTEM 1991	CIN SYSTEM	INTERPRETATION
Negative for intraepithelial lesions or malignancy	Within normal limits	Normal	No abnormal cells
ASC-US (atypical squamous cells of undetermined significance)	ASCUS (atypical squamous cells of undetermined significance)		Squamous cells with abnormalities greater than those attributed to reactive changes but that do not meet the criteria for a squamous intraepithelial lesion
ASC-H (atypical squamous cells, cannot exclude HSIL)
LSIL (low-grade squamous intraepithelial lesions)	LSIL (low-grade squamous intraepithelial lesions)	CIN 1	Mildly abnormal cells; changes are almost always due to HPV
HSIL (high-grade squamous intraepithelial lesions) with features suspicious for invasion (if invasion is suspected)	HSIL (high-grade squamous intraepithelial lesions)	CIN 2/3	Moderately to severely abnormal squamous cells
Carcinoma	Carcinoma	Invasive squamous cell carcinoma; invasive glandular cell carcinoma (adenocarcinoma)	The possibility of cancer is high enough to warrant immediate evaluation but does not mean that the patient definitely has cancer

^a From reference 1.

Additional guidelines exist for managing patients with abnormal cytology results and/or a positive HPV test. In a woman with a normal Pap smear but positive high-risk HPV test, HPV genotyping should be considered. If HPV genotyping is not performed or it is not HPV 16/18, then the woman should return in a year to determine if the HPV infection is persistent. However, if the genotype is HPV 16/18, colposcopy should be considered. ASC-US with a negative HPV testing indicates only repeat testing in a year. A woman with ASC-US and a positive HPV test, LSIL, or HSIL should proceed to colposcopy. If the biopsy obtained during colposcopy is abnormal, further treatment is needed, which includes LEEP, cryotherapy, laser therapy, or cone biopsy.

6. HPV infection requires genital contact. Thus, abstinence or a monogamous relationship with an uninfected partner will prevent HPV infection. Condom use has been shown to reduce transmission, but it does not completely prevent infection. Two vaccines are available for the prevention of HPV infection. Both vaccines protect against HPV 16 and 18 which together cause ~70% of cervical and anal cancers. One of the vaccines also prevents infection with HPV types 6 and 11, which cause ~90% of genital warts. The quadrivalent vaccine requires three injections over 6 months and is approved for females and males aged 9 to 26. Likewise, the bivalent vaccine requires three injections over 6 months, but is approved only for females aged 9 to 25. Neither vaccine has been shown to provide protection against other high-risk HPV types, which is why vaccinated women should continue to get routine cervical cancer screening by Pap smear and HPV molecular detection.

The HPV vaccines are composed of HPV surface components that aggregate to form virus-like particles (VLPs). These VLPs contain no DNA, so there is no risk of developing HPV infection from vaccination. However, the VLPs stimulate antibody production, which protects the host against future HPV infections with the specific HPV types in the vaccine. Longitudinal outcome studies are still being performed on these relatively new vaccines, but the data to date indicate nearly 100% protection from persistent HPV 16/18 infections and the associated precancerous changes up to 8 years post-vaccination. HPV vaccination is recommended for 11- to 12-year-old girls and boys. In addition, females aged 13 to 26 and males aged 13 to 21 should receive the vaccine series if not previously vaccinated. Men who have sex with men should receive the vaccine through 26 years of age.