DR. KAHN is associate professor of pediatrics, division of adolescent medicine, Cincinnati Children's Hospital Medical Center,
Cincinnati, Ohio.
DR. HILLARD is professor and chief, gynecology, division of adolescent medicine, Cincinnati Children's Hospital Medical Center.
Staff editors: KAREN BARDOSSI, Senior Editor, and JOHN BARANOWSKI, Editor, Contemporary Pediatrics
Dr. Kahn, the manuscript reviewers, and staff editors have nothing to disclose in regard to affiliations with, or financial
interests in, any organization that may have an interest in any part of this article.
Dr. Hillard is a consultant for Merck, Procter and Gamble, Wyeth-Ayerst, and GlaxoSmithKline; has received research support
from Berlex, Wyeth-Ayerst, and Duramed; and is on the speakers' bureaus of 3M, Barr Laboratories, Berlex, Merck, Pharmacia-Upjohn,
Pfizer, Organon, Ortho-McNeill, Tap, and Wyeth-Ayerst.
Human papillomavirus (HPV) infection is a highly prevalent sexually transmitted infection (STI) that adolescents often acquire
soon after sexual initiation. It is usually transient in adolescents, in whom significant premalignant cervical lesions are
rare, but persistent infection with cancer-associated (high-risk) HPV types can progress to cervical cancer over time. In
the first part of this article (March 2006) we reviewed HPV infection and its clinical consequences, recent data about the natural history of HPV infection
in adolescents, and technologies for detecting HPV infection.
Cervical cancer is essentially a preventable disease when appropriate cervical cytology screening is performed. New screening
guidelines can facilitate prevention, and vaccines in development show great promise. As a pediatrician, you will play an
increasingly important role in protecting your adolescent patients from HPV-related disease.
Update on cervical cancer screening guidelines
In light of new data concerning the epidemiology and natural history of HPV and the availability of liquid-based Pap tests
and HPV DNA tests, new guidelines for Pap screening and management of abnormal cytologic findings have been developed with
input from professional organizations. The American Cancer Society (ACS) took the lead in convening an expert panel to review
the available evidence and develop new screening guidelines.1 The American Society for Colposcopy and Cervical Pathology (ASCCP) and The American College of Obstetricians and Gynecologists
(ACOG) recently published management guidelines.2,3 Here, we briefly summarize guidelines concerning initiation of screening and follow-up of abnormal results in adolescents
and discuss the rationale for those guidelines.
Initiation of cervical cytology screening
In formulating recommendations about initiation of screening, the ACS committee members considered data demonstrating that:
- most HPV infections in adolescents are transient
- the great majority of mild cervical abnormalities regress
- the risk of developing a high-grade squamous intraepithelial lesion (HSIL) is low even in those adolescents infected with
high-risk HPV types
- persistent infection with high-risk HPV types takes years to progress to cervical intraepithelial neoplasia (CIN) 3 and cancer.1
The ACS committee concluded that the risk of missing a high-grade cervical lesion is very low until at least three to five
years after initial infection with HPV. The members were therefore concerned that practitioners may be initiating cytology
screening too early in adolescents, leading to overdiagnosis of mild abnormalities that would have resolved spontaneously
and to unnecessary diagnostic procedures and treatments.1
For this reason, ACS guidelines recommend starting screening approximately three years after initiation of vaginal intercourse,
or by 21 years of age. Thereafter, the guidelines recommend annual screening if a traditional Pap smear is used and every
two years if liquid-based Pap tests are used. The age limit of 21 years was chosen to ensure screening of young women who
might be unwilling or unable to acknowledge sexual activity or abuse.
The ACOG recommendations endorse the ACS guidelines but also note that clinicians may choose to begin screening earlier in
young women they consider to be at high risk of CIN—based on sexual behaviors or a history of sexual abuse, for example—or
who are unlikely to comply with recommendations for screening and follow-up.
In our practice, we repeat Pap screening annually in adolescents if the Pap test remains negative for intraepithelial lesions
or malignancy. We have made the decision to screen annually, even though we use liquid-based Pap testing, because many of
our patients are at high risk of abnormal Pap tests and do not return consistently for Pap screening or follow-up.
If a specimen is unsatisfactory for evaluation because no endocervical cells are present, we repeat the Pap test. If the Pap
is negative for intraepithelial lesions but suggests an infectious organism such as Trichomonas vaginalis, we evaluate the patient for infection and repeat the Pap in one year. If the Pap is negative for intraepithelial lesions
but shows reactive cellular changes associated with inflammation, we evaluate for infection and repeat the Pap in two or three
months. If that result is normal, we repeat the Pap in one year.
Both ACS and ACOG emphasize that adolescents who may not need cervical cytology screening should still obtain preventive health
care, including contraception and screening for STI. ACOG recommends annual gynecologic visits beginning at approximately
13 to 15 years of age to address preventive health concerns and assess gynecologic and sexual history in a confidential setting.
These visits help determine the appropriate date for initiation of cervical cytology screening.3
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
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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
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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
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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
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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.
