Follow-up of abnormal cervical cytology

In formulating recommendations for follow-up of abnormal Pap results, the ASCCP considered recent data concerning the natural history of HPV infection in women as well as new technologies such as HPV DNA and liquid-based Pap tests. A number of studies have shown that HPV DNA testing has higher sensitivity than Pap testing for detecting moderate or severe CIN. Results of the ASC-US-LSIL Triage Study (ALTS), a randomized multicenter trial designed to compare different management strategies for women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL), demonstrated that HPV testing to augment ASC-US cytology was as sensitive as immediate colposcopy in detecting HSIL and substantially decreased the number of women referred for colposcopy.⁴

Other potential advantages of HPV testing as an adjunct to cervical cytology include:

• sparing women with abnormal cytology results an additional clinical examination for repeat cytology and the anxiety of waiting for a repeat result
• decreasing the risk of loss to follow-up because repeat cytology is not needed
• decreasing the expense of repeated cytologic testing and office visits.

The ASCCP guidelines therefore recommend that reflex HPV DNA testing for women with ASC-US should be performed when liquid-based cytology is used or when co-collection for HPV DNA testing can be done (that is, an HPV DNA test is performed only if the Pap shows ASC-US), and that all women who test positive for high-risk HPV DNA should be referred for colposcopic evaluation. In contrast, HPV testing does not seem to be useful in making decisions about triage to colposcopy in women with LSIL cytology because more than 80% of women with LSIL are positive for high-risk HPV.⁴

HPV DNA testing has also been approved by the Food and Drug Administration (FDA) as an option for primary screening, in addition to cervical cytology testing, for women older than 30 years. The ACS and ASCCP guidelines concur and state that, in this age group, women with negative HPV and negative Pap results should not be rescreened for three years.^1,5 HPV DNA testing is not currently recommended for primary screening of adolescent and young adult women because HPV infection is so common and usually transient in this age group.

Figure 1: Management of adolescents with ASC

Figures 1 and 2 present algorithms adapted from the ASCCP guidelines to guide follow-up of atypical squamous cells (ASC) and squamous intraepithelial lesion (SIL) in adolescents. In healthy adolescents with initial results of ASC-US (Figure 1), one may perform either reflex HPV testing or a repeat Pap test at four to six months. If the HPV test is negative for high-risk HPV, the adolescent may return to routine screening. If it is positive for high-risk HPV, colposcopy is recommended. If the repeat Pap test is abnormal, colposcopy is recommended. If the repeat Pap test is normal, a second Pap test is recommended in four to six months. If this Pap test is abnormal, colposcopy is recommended; if it is normal, the adolescent may return to routine screening. Adolescents with a Pap test result of ASC-H (atypical squamous cells, cannot exclude high-grade SIL) should be referred to colposcopy because of the significant risk of underlying moderate or severe CIN.

Figure 2: Management of adolescents with SIL

The ASCCP guidelines recommend referral for colposcopy for all adult women with LSIL but note that follow-up with either HPV DNA or Pap testing instead of colposcopy is reasonable in adolescents, because of the benign nature of LSIL in this population (Figure 2). In healthy adolescents with Pap results of LSIL, one may either perform HPV DNA testing 12 months after the initial Pap test or repeat Pap testing at six months. Thereafter, recommendations are similar to those for ASC-US. If the adolescent has a positive test for high-risk HPV, she is referred to colposcopy; if the test is negative, however, she may return to routine screening. Alternatively, she must have two sequential negative Pap tests to return to routine screening. Adolescents with HSIL should be referred to colposcopy because of the significant risk of underlying moderate or severe CIN.

Special situations

We recommend that young women who have a diagnosis of HIV infection or other conditions that cause immunocompromise undergo Pap screening twice in the first year after diagnosis and then annually if results are normal.¹ For those who report a history of sexual abuse with vaginal penetration, we recommend initial screening, when feasible, by a provider who has experience managing young women with a history of sexual assault and then yearly follow-up if results are normal.¹ Last, for young women with developmental delay, no history of consensual sexual intercourse, and no concern for sexual abuse, we recommend that screening begin at approximately 21 years of age and then every two or three years if results remain normal.

Preventing HPV-related disease with vaccines

Over the past 15 years, remarkable progress has been made in developing HPV vaccines that induce virus-neutralizing antibody and provide protection against HPV acquisition.^6,7 Vaccines in development are virus-like particles, or VLPs, which are recombinant viral capsids. Because they are created by inducing expression of the major HPV capsids protein L1 in eukaryotic cells, they are identical morphologically to HPV virions. Because they contain no viral DNA, they cannot transmit virus or cause disease.

The two vaccines being evaluated in large, phase-III clinical trials appear to be safe, well-tolerated, and highly effective in preventing HPV acquisition, abnormal Pap tests, and CIN.^8,9 Both are likely to be licensed by the Food and Drug Administration within the next year or two. One of the vaccines in development targets HPV types 6, 11, 16 and 18⁹ ; the other, HPV types 16 and 18.⁸

Both vaccines have the potential to be highly effective strategies for primary prevention of HPV-related disease. Almost all cases of recurrent respiratory papillomatosis and approximately 90% of anogenital warts are caused by HPV types 6 and 11; approximately 70% of cervical cancer is caused by types 16 and 18. Widespread HPV vaccination could also reduce the substantial costs associated with cervical cancer screening and HPV-related disease—not only because it should decrease the incidence of abnormal Pap tests but also because it may permit longer intervals between screening Pap tests.

A number of questions remain concerning HPV vaccine delivery. Because these vaccines would, ideally, be administered before sexual initiation, the target group is likely to include children between 9 and 12 years of age, for whom parental consent for vaccination will likely be required. Parental acceptance of vaccination will be important, therefore, for widespread vaccine uptake. Although a few groups have voiced opposition to HPV vaccines, studies demonstrate consistently that health care providers, parents, and adolescents consider the vaccines to be acceptable.^10-12

Pediatricians clearly will play an essential role in vaccine delivery because early adolescents are more likely to visit a pediatrician than any other provider and because a pediatrician's recommendation for vaccination strongly influences a parent's or adolescent's decision. In recent studies, pediatricians report that vaccine safety and efficacy are the most important features of HPV vaccines and that parental refusal or reluctance to accept HPV vaccination would be the principal barrier to recommending these vaccines.¹⁰

Ensuring adolescent adherence to the vaccination schedule will present a challenge. Achieving the required series of three immunizations may be difficult in the preadolescent and adolescent population, as was observed upon introduction of the hepatitis B vaccine. Moreover, adolescent and adult women who have been vaccinated may believe that they do not need Pap screening because they are protected from cervical cancer. As noted, however, the vaccines in development target only approximately 70% of HPV types responsible for cervical cancer. It will be critical for women to continue regular Pap screening, even if it is determined that the interval between screenings can be lengthened safely.

Last, questions remain about the efficacy of HPV vaccines in preventing HPV-related diseases other than CIN (such as genital warts), their efficacy in preventing HPV-related diseases in men, and the duration of protection after vaccination. Large-scale studies are under way to provide answers to some of these questions.

Your role in preventing HPV-related disease

Key points for educating adolescents about HPV

Virtually all cervical cancer should be avoidable if at-risk women participate in Pap screening and HPV testing and if precancerous lesions detected by screening are treated. Vaccines to prevent HPV infection may become a highly effective primary prevention strategy, but the vaccines in development will not replace Pap screening. You will, therefore, have to continue to assess adolescents for risk of HPV-related disease and follow current screening recommendations. Strategies to promote health and prevent HPV-related disease in adolescents should focus on increasing the adolescent's knowledge of new cervical cancer prevention technologies and guidelines and ensuring that she adheres to recommendations for both screening and follow-up of abnormal results.

Assessing adolescent risk and performing screening as indicated. Ask all adolescents about their sexual history in a confidential setting, communicate the recommendation about initiating Pap screening to adolescents who are seeking care for other reasons (such as STI screening), and either perform screening when indicated or refer the patient to other providers.

Educating adolescents about HPV. Although new technologies such as liquid-based Pap testing, HPV DNA testing, and HPV vaccines have the potential to improve women's reproductive health from adolescence through adulthood, using the new technologies may present specific challenges for adolescents. The primary challenge is poor understanding of HPV infection, Pap testing, and the complex associations between HPV, abnormal Pap tests, and cervical cancer.¹³ You should be prepared to provide accurate information about HPV infection and to answer your patients' questions. The table summarizes "Key points for educating adolescents about HPV."

The Centers for Disease Control and Prevention has developed excellent, evidence-based educational resources for providers and the general public about HPV infection and HPV DNA testing (see "Online educational resources on HPV"). In addition, the American Social Health Association Web site provides outstanding materials about HPV for women (www.ashastd.org) and specifically for adolescents (www.iwannaknow.org).

Online educational resources on HPV

If one of your adolescent patients needs colposcopy, refer her if possible to a program that can meet the specific needs of adolescents—a program, for example, that provides in-depth education, encourages patient-parent communication during the consent process, and pays careful attention to follow-up care. You may be asked to perform testing for STIs, such as gonorrhea or infections caused by Chlamydia or Trichomonas, before the procedure. If such tests are positive, the patient should be treated before colposcopy to minimize the risk of pelvic infection after cervical biopsy.

You can explain that a colposcopic evaluation involves examination of the vulva, perineum, perianal area, vagina, and cervix using magnification and a weak acetic acid (vinegar) solution. The most abnormal areas of the vulva, vagina, or cervix are biopsied to determine if there is an underlying abnormality that may progress to cancer.

Assisting with decision-making. Your challenge is to help adolescents make informed, healthy decisions about new technologies as they take on increasing responsibility for their health care. Because the development of guidelines for Pap and HPV testing is an ongoing process and different guidelines have been issued by various organizations, some experts have advocated shared decision-making between physician and patient regarding screening and follow-up procedures. However, adolescents vary greatly in their cognitive and psychosocial development, both of which may affect their ability to make informed decisions about health-related behaviors. Some patients may find it difficult to make an informed choice about such a complex issue, given their evolving cognitive ability and poor understanding of HPV infection. They need guidance and support from you about the options available to them. Adolescents prefer to receive this guidance through honest, open discussion with their physician in a confidential setting.

Parental involvement can be valuable because parents are an important and trusted source of information and support for adolescents who are making health decisions. Because HPV is an STI, however, it is important to maintain confidentiality if that is what the patient desires.

Addressing psychosocial responses to abnormal results. As HPV DNA testing is incorporated into cervical cancer screening guidelines, many adolescent girls will learn that they are HPV-positive or that an abnormal Pap test indicates HPV infection. In studies of both adults and adolescents, HPV testing has been associated with anxiety, distress, and anticipated social stigma.¹³ These responses may compromise adolescents' decisions about future screening and follow-up.

Alternatively, testing may lead to a sense of empowerment through knowledge of results and self-confidence to prevent future disease by means of healthy behaviors and regular screening. Responses to Pap and HPV test results and decisions about future screening are influenced by variables such as counseling by the pediatrician, personal health experiences, and family history of cancer.

When communicating test results to an adolescent, you may be able to reduce harmful psychosocial consequences of abnormal results by providing accurate information about the results and their implications; using a factual, nonjudgmental and supportive approach; and exploring personal and family factors that may prompt an adverse response to test results. You may be able to promote positive health outcomes by helping the adolescent to develop effective coping skills and empowering her to make behavioral changes to reduce the risk of cervical cancer. Such changes might include stopping smoking, adopting safer sexual behaviors, and undergoing regular Pap screening.

Promoting adherence to screening and follow-up recommendations. Adolescents report that they are more likely to adhere to screening and follow-up recommendations if their physician communicates well, provides confidential care, and performs a pelvic examination gently. You may be able to promote adherence by providing in-depth, developmentally appropriate, and culturally sensitive education about HPV infection and Pap screening and reinforcing your counseling with written information. Parents also can be helpful in reinforcing prevention messages and ensuring that the adolescent comes in for appointments—if the adolescent gives permission for the parent to be involved.

Assess, screen, educate, and, perhaps, vaccinate

HPV infection is extremely common and responsible for substantial morbidity and mortality worldwide. Although infection occurs rapidly after sexual initiation, it is usually transient in adolescents, and significant premalignant cervical lesions are rare. New guidelines recommend that Pap testing begin three years after sexual initiation or by 21 years of age; HPV DNA testing is a new option for the triage of women with ASC-US Pap results. Vaccines are likely to emerge as a highly effective primary prevention strategy, but will not replace Pap screening. Pediatricians will play an important role in assessing risk of HPV-related disease among adolescent patients, following current screening recommendations, and educating patients and their parents about HPV.

REFERENCES

1. Saslow D, Runowicz C, Solomon D, et al: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342

2. Wright TC, Cox JT, Massad LS, et al: 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120

3. ACOG Practice Bulletin No. 45. Cervical Cytology Screening. Obstet Gynecol 2003;102:417

4. The ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188(6):1383

5. Wright TC, Jr., Schiffman M, Solomon D, et al: Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103(2):304

6. Christensen ND: Emerging human papillomavirus vaccines. Expert Opin Emerg Drugs 2005;10(1):5

7. Kahn JA, Bernstein DI: Human papillomavirus vaccines and adolescents. Curr Opin Obstet Gynecol 2005;17(5):476

8. Harper DM, Franco EL, Wheeler C, et al: Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: A randomised controlled trial. Lancet 2004;364(9447):1757

9. Villa LL, Costa RL, Petta CA, et al: Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6(5):271

10. Kahn JA, Zimet GD, Bernstein DI, et al: Pediatricians' intention to administer human papillomavirus vaccine: The role of practice characteristics, knowledge, and attitudes. J Adolesc Health 2005;37(6):502

11. Zimet GD, Mays RM, Sturm LA, et al: Parental attitudes about sexually transmitted infection vaccination for their adolescent children. Arch Pediatr Adolesc Med 2005;159(2):132

12. Zimet GD, Perkins SM, Sturm LA, et al: Predictors of STI vaccine acceptability among parents and their adolescent children. J Adolesc Health 2005;37(3):179

13. Kahn JA, Slap GB, Bernstein DI, et al: Psychological, behavioral, and interpersonal impact of human papillomavirus and pap test results. J Womens Health (Larchmt) 2005;14(7):65

What you need to know about HPV

Human papillomavirus (HPV) is a virus that most people are exposed to, much like a virus that causes a “cold,” except that HPV is usually spread through sexual contact. It can be spread through genital-genital or oral-genital contact; sexual intercourse is not necessary to spread the virus. Most people get genital HPV infection at some point in their life. If a woman is diagnosed with HPV infection or an HPV-related disease, it is difficult to know for certain when she acquired the infection. Here is more that you should know about HPV:

• HPV is not the same as human immunodeficiency virus (HIV), the virus that causes AIDS.
• HPV infection usually goes away on its own because the immune system clears the virus from the body.
• 4HPV usually does not cause any symptoms or disease, but sometimes it causes genital warts, abnormal cells in the cervix (the outer end of the uterus), or cancer of the cervix. Genital warts and cervical cancer are each caused by different types of HPV. At some point, your physician will recommend that you have a Pap test. The Pap test is done to find out if you have abnormal changes in the cells of your cervix that are caused by HPV and may eventually turn into cervical cancer. If you have an abnormal Pap test, that usually means you are infected with HPV. You may need to return for more testing and possibly be treated to prevent cervical cancer.
• Only a very small percentage of women with the HPV types that cause cervical cancer, and whose infection persists (doesn’t go away), go on to develop cancer. Cervical cancer is extremely rare in adolescent and young adult women.
• Physicians do not routinely screen adolescents for HPV, but your doctor may do an HPV test if your Pap test is abnormal, to help decide whether more evaluation is needed.

The best way to prevent HPV infection and its consequences is not to have sexual intercourse (abstinence). If you do have sex, you can lower your risk of HPV infection by limiting the number of people with whom you have sex and by having sex with partners who have had no or few sex partners themselves. Consistent and correct condom use is also important. Although condoms do not completely prevent transmission of HPV, they prevent HPV-related diseases and other sexually transmitted infections such as Chlamydia and HIV. You can also reduce the risk of HPV infection, genital warts, and cervical cancer by avoiding smoking. Vaccines that prevent some types of HPV may be available in the next year or two.