The method for cervical screening worldwide has been the Papanicolaou (Pap) test, in which desquamated cells in cervical mucus are microscopically assessed for cytologic abnormalities associated with cervical dysplasia or malignancy. While the Pap test has been used for decades, our expanding knowledge of the role of human papillomavirus (HPV) in cervical dysplasia and malignancy has profoundly altered our approach to screening. Specifically, the addition of assessing for the presence of high-risk HPV DNA in liquid-based Pap smear samples has markedly improved our screening of women given the well-recognized limitations of cervical cytology alone. In addition, the recently developed HPV vaccines have been shown to be effective preventative tools, especially when provided to adolescents before the onset of sexual activity.⁵

New guidelines have recommended changes that reduce the frequency of cervical cancer screening for certain populations.⁶ For example, screening should now begin at age 21 and should be performed every 2 years instead of annually in women ages 21 to 29. An important reason for these recent changes is the recognition that screening women younger than 30 years of age on an annual basis can lead to unnecessary and potentially harmful cervical evaluations and treatments for women who are actually at very low risk for developing cervical cancer. These changes are based on our expanding knowledge of the immune response to HPV infections and the implications for the development and regression of dysplastic cervical lesions.

In pregnant women, cervical screening is geared to a different clinical process than that which is applied to the non-pregnant population.⁷ In non-pregnant women, the detection of cervical cytologic abnormalities frequently leads to colposcopy and biopsy and in many cases, to extirpation of the dysplastic lesion to prevent the development of malignancy.

In pregnant women, the only indication for treatment of cervical neoplasia is a diagnosis of invasive cervical cancer.⁷ This is because progression of cervical dysplasia to frank malignancy—even in cases of moderate to severe dysplasia—is highly unlikely during pregnancy.⁸ In addition, cervical biopsy in pregnancy is associated with a higher likelihood of complications, especially increased bleeding, as a result of the markedly increased vascularity of the pregnant cervix compared to the non-pregnant cervix.

As such, cervical surveillance during pregnancy is geared not to the detection of cervical dysplasia but rather to the direct detection of invasive cervical cancer. Wetta and colleagues recently showed that pregnant women with atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) rarely have colposcopically suspected CIN 2, 3 or malignancy that warrants biopsy.² Accordingly, it is appropriate to defer colposcopy in such cases until at least 6 weeks postpartum.

While cervical cytology screening is a routine component of prenatal care in the US, the role of HPV DNA testing in cervical surveillance during pregnancy is less clear.⁹ Rombaldi and colleagues reported that perinatal transmission of HPV from mother to fetus occurred in almost 25% of the cases studied, thus presenting another potential clinical risk for HPV.¹⁰ Nonetheless, there does not appear to be a current role for HPV DNA testing in the management of abnormal cervical cytology results during pregnancy. For example, ASC-US cytology results associated with positive high-risk HPV would be managed in a manner similar to the same cytology outcome with a negative HPV DNA test. In the older pregnant woman, positive high-risk HPV DNA test results would similarly not alter the management of ASC-US or LSIL cytology. In any pregnant woman, the detection of high grade squamous intraepithelial lesion (HSIL) or carcinoma cells would clearly warrant colposcopy regardless of the HPV status.

Finally, the use of the bivalent or quadrivalent vaccine is contraindicated during pregnancy, although there is no evidence of any teratogenic effect of either vaccine on developing embryos or fetuses.

KEY POINTS
1. Cervical cancer screening should be a routine component of prenatal care in order to exclude invasive cervical cancer.

2. Colposcopy can be performed throughout pregnancy to determine whether high-grade lesions are present.

3. In cases of suspected low-grade disease, colposcopy and cervical biopsies can be deferred until the postpartum period.

4. In cases of suspected high-grade disease, cervical biopsy can be performed. However, endocervical curettage is absolutely contraindicated throughout pregnancy.

5. Although HPV DNA testing is a valuable triage tool in other clinical situations, a positive HPV DNA test does not alter the immediate management of cervical cytology results obtained during pregnancy.

6. The use of vaccines for the prevention of HPV-associated disease is contraindicated during pregnancy.

The Advisory Committee on Immunization Practices (ACIP), a Federal committee coordinated by the CDC, makes recommendations for use of vaccines in the US. They recently made provisional recommendations for the use of both the HPV quadrivalent vaccine in males and the HPV bivalent vaccine in females. The bivalent HPV vaccine (HPV 16, 18) was approved in October 2009 by the FDA for the prevention of cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 or greater and adenocarcinoma in situ, and CIN 1 caused by HPV 16 and 18 in females 10 to 25 years of age.¹ The quadrivalent HPV vaccine also received approval by the FDA in October for use in boys and men 9 to 26 years of age for the prevention of genital warts caused by HPV 6 and 11.²

In October 2009, ACIP voted to recommend the "routine administration" of both the quadrivalent and the bivalent HPV vaccines in girls 11 to 12 years of age. In addition, the recommendations include a "catch-up" vaccination for girls and young women who have not previously been vaccinated in the approved age groups (9 to 26 years for the quadrivalent vaccine and 10 to 25 years for the bivalent vaccine). A recommendation for the "routine use" of a vaccine by the ACIP means that all health care professionals should offer the vaccination to their patients.

In contrast to what is recommended for girls and young women, ACIP voted to recommend the "permissive use" of the quadrivalent HPV vaccine for boys and young men. “Permissive use” denotes a substantial difference in the strength of the recommendation since it means that decisions on whether to immunize are left up to the health care professional taking care of the patient. The reasons for the difference in the strength of the recommendations is partly due to the fact that the vaccines are approved for protection against cancer and high-grade CIN in females, but the quadrivalent vaccine is approved only for the prevention of genital warts in males. Moreover, the health economic modeling of vaccinating all males against HPV has been found to be unfavorable.³

There is considerable evidence that infection with high-risk types of HPV plays an important role in the development of head and neck squamous cell carcinomas (HNSCC). In 2008, an estimated 47,500 individuals were diagnosed with head and neck cancer in the US and approximately 11,260 died of this disease. Most of these cancers are squamous cell carcinomas. Tobacco and alcohol use are the primary risk factors for HNSCC. In addition to these traditional risk factors, infection with high-risk types of HPV, particularly HPV 16, appears to be an independent risk factor for a subset of HNSCC. HPV-associated HNSCC usually involve the oropharynx, specifically the palatine and lingual tonsils. The odds ratio for the association between HPV and tonsillar cancer is 15.1, whereas it is only 4.3 for the association of HPV and oropharyngeal cancer in general, and only 2.0 for the association of oral cancer and HPV.⁴

HPV-associated carcinomas have a unique histological appearance. Most HNSCC are moderately differentiated keratinizing squamous cell carcinomas, whereas HPV-associated oropharyngeal squamous cell carcinomas (OPSCC) are poorly differentiated, non-keratinizing, and have a basaloid appearance. The HPV-associated cancers also have a distinct molecular profile compared to non-HPV-associated carcinomas. HPV-associated cancers typically do not have p53 mutations, and overexpress p16 rather than show loss of p16.

The major risk factors for HPV-associated HNSCC include multiple sexual partners (both oral and vaginal), a history of genital warts, and early age at first sexual intercourse.^{5, 6} Moreover, data from the Surveillance, Epidemiology and End Results (SEER) registry (the National Cancer Institute's tumor registry) shows an increased risk of tonsillar cancer in women with a history of cervical cancer as well as in the husbands of women with a history of CIN or cervical cancer.⁷

In addition to having a distinctive molecular profile and histological appearance, HPV-associated cancers have a different prognosis. HPV-positive HNSCC have a better prognosis than HNSCC not associated with HPV. They respond better to induction chemotherapy and to chemoradiation and have an overall 2-year survival rate of 95%, compared to 62% for non-HPV-associated carcinomas.⁸

The 2006 Consensus Guidelines published by the American Society for Colposcopy and Cervical Pathology (ASCCP) recommend that women in the general population with low-grade squamous intraepithelial lesions (LSIL) should be referred for colposcopy.⁹ This recommendation was based on the fact that most women in the general population with LSIL will be high-risk HPV DNA positive and therefore using HPV status to determine which women with LSIL require colposcopy is simply not efficient. However, because of the decline in the prevalence of HPV that occurs as women age, it is expected that the prevalence of high-risk HPV infections in older women with LSIL is low enough that triage using high-risk HPV DNA testing is an efficient approach to managing postmenopausal women with LSIL. Therefore, guidelines recommend that postmenopausal women with LSIL be managed in the same fashion as women in the general population with atypical squamous cells of undetermined significance (ASC-US). This means that "reflex HPV DNA testing" is the preferred approach to determining which of these women require colposcopy whenever liquid-based cytology is used.

It should be stressed, however, that there is relatively little data on the prevalence of high-risk HPV DNA positivity in women with LSIL in the US and that the 2006 Consensus Guidelines are based on inference from studies of postmenopausal women with ASC-US. One recent study from Italy reported that 93% of postmenopausal women with LSIL were high-risk HPV DNA positive.¹⁰

1. FDA approves a new vaccine for the prevention of cervical cancer. US Food and Drug Administration Web site. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187048.htm.Updated on October 19, 2009.
2. FDA approves new indication for Gardasil to prevent genital warts in men and boys. US Food and Drug Administration Web site. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187003.htm. Updated on October 16, 2009.
3. Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ. 2009;339:b3884.
4. Hobbs CG, Sterne JA, Bailey M, et al.Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol. 2006;31(4):259-266.
5. Kreimer AR, Clifford GM, Boyle P,et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-475.
6. Gillison ML, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407-420.
7. Hennessey PT, Westra WH, Califano JA. Human papillomavirus and head and neck squamous cell carcinoma: recent evidence and clinical implications. J Dent Res. 2009;88(4):300-306.
8. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-269.
9. Wright TC, Jr., Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007;197(4):346-355.
10. Piccoli R, Mandato VD, Lavitola G, et al. Atypical squamous cells and low squamous intraepithelial lesions in postmenopausal women: implications for management. Eur J Obstet Gynecol Reprod Biol. 2008;140(2):269-274.