J. Thomas Cox, MD

Dr. Einstein reports that Montefiore Medical Center has received payment from Roche and Hologic for time he spent as an advisor or educational speaker. In some cases, his travel has been paid for when required for meetings. In addition, Dr. Einstein reports that Montefiore has received grant funding from Roche, Hologic, and Becton-Dickinson for research-related costs of clinical trials that he has been the overall or Montefiore principal investigator.

Dr. Cox reports that he is a consultant to OncoHealth; a member of the Scientific Advisory Boards for Roche and Hologic; a speaker for Roche; and on the Data and Safety Monitoring Board for HPV vaccines for Merck.

Cervical cancer screening is necessarily complex, and guidelines must change fairly frequently as our understanding of the natural history of HPV infection and cervical cancer continues to evolve. Up-to-date guidelines enhance our ability to detect cervical intraepithelial neoplasia and cancer early and manage them appropriately.

In April 2013, the American Society for Colposcopy and Cervical Pathology (ASCCP) updated guidelines for the management of abnormal cervical cytology and cervical cancer precursors for the first time since 2006.¹ This update follows new cervical cancer screening guidelines published in 2012 by the ACS/ASCCP/ASCP,² the USPSTF,³ and the American College of Obstetricians and Gynecologists⁴ (and reported in OBG Management in June 2012⁵).

For many clinicians, all these modifications amount to a dizzying “sea change” in the way they have been screening and managing patients to prevent cervical cancer. Clinicians often express frustration with the guidelines, both for their complexity and for what seems like all-too-frequent changes. Do they really need to change … again? Do they really need to get even more complex? And what about them is really new?

This article addresses these questions by reviewing the guidelines and their updates in more depth. For a specific answer to the question of “What’s new?” see sidebar below.

Did the guidelines really need to change … again?

Cervical cancer screening tests—be they the Pap test or a human papillomavirus (HPV) test—are not as clear-cut as other tests used to screen for sexually transmitted infections or their effects. We treat a patient whenever her gonorrhea or Chlamydia test is positive, for example. However, other than cytology classified as high-grade (ie, HSIL), which may prompt immediate treatment in women 25 years and older by “see-and-treat” loop electrosurgical excision procedure (LEEP), neither cervical cytology nor HPV testing is sufficiently specific for present disease (cervical intraepithelial neoplasia [CIN] 3 or cancer) to warrant treatment without a diagnostic work-up. That’s because the cause of cervical cancer (infection with HPV) usually does not produce CIN 3 or cancer, and the cell changes that it does produce most often (atypia and koilocytosis) are very common. And other cervical-vaginal changes associated with hormonal fluctuations, tampons, intercourse, and so on, may result in cervical cytologic changes unrelated to HPV and, therefore, do not represent a risk for cervical cancer.

How can we best sort out who needs to be evaluated without under- or overdoing it? When we find CIN, some of which is destined to progress and some not, how do we reduce the risk of overtreatment without increasing the likelihood that some will progress to cancer? If we have treated CIN or adenocarcinoma in situ (AIS), how do we make sure there is no recurrence without risking over-management and potential overtreatment?

The first thing we do is ensure that we use our best clinical judgment and also respect the informed wishes of the patient. Because the guidelines are based on the best available data, and on expert opinion when data are lacking, guidelines developed through a consensus process provide a framework for care that is optimal for most women at each phase of their lives. This knowledge can help the clinician—and often the patient—make the best-informed decisions.

Do guidelines really need to get even more complex?

Consider the myriad management decisions that confront us in the field of cervical cancer screening, and the potential result of each choice. Even when cervical screening involves cytology alone, there are five major categories for abnormal results, each associated with a different level of risk requiring a unique level of management:

• atypical squamous cells – undetermined significance (ASC-US)
• atypical squamous cells – cannot rule out a high-grade lesion (ASC-H)
• atypical glandular cells (AGC)
• low-grade squamous intraepithelial lesion (LSIL)
• high-grade squamous intraepithelial lesion (HSIL).

Add in HPV testing with cervical cytology for women 30 years and older, and there is one more abnormal category—normal Pap/ HPV-positive. And these categories just cover initial management. Also needed are guidelines for appropriate follow-up of women who undergo colposcopy for each abnormal cytologic result when no CIN 2, CIN 3, or AIS is found that requires treatment, as well as guidelines for managing women following treatment when high-grade histology is found.

As our understanding of the natural history of HPV and cervical oncogenesis has increased, it has become clearer that we must further adjust management decisions on the basis of age, essentially creating many parallel sets of guidelines for women aged 21 to 24, 25 to 29, and 30 years and older.

Yes, cervical screening and management are complex. We are fortunate that the Internet and new “apps” for smartphones give us easy access to guidelines for most of the potential combinations of clinical findings and results. The guideline algorithms are available at www.asccp.org, and full explanatory articles are available at www.jlgtd.com and www.greenjournal.org (comprehensive apps are available for download for almost every smartphone device).

Remember, it is impossible to create guidelines for every possible clinical situation, so clinical judgment must always be paramount when applying guidelines to individual patients.¹

What are the major changes of the latest set of guidelines and its update?

Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–846. [Also published in J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.]

Let’s start by focusing on how the experts crafted the 2012 guidelines. New evidence to guide decisions about the management of abnormal screening tests, CIN, and AIS emerged in 2012 from a review of the world literature and from analyses of a large 7-year clinical database (1.4 million women) at the Kaiser Permanente Northern California Medical Care Plan, conducted in collaboration with scientists from the National Cancer Institute.¹

Most of the 2006 guidelines remain valid, but new evidence has modified some of the guidelines and created others where gaps existed. Guideline developers recognized that cervical cancer prevention is a process that entails both benefits and potential harms, and that the potential risks cannot be reduced to zero with the strategies currently available. Attempts to achieve zero risk could result in unbalanced harms, including overtreatment.

Defining acceptable risk levels

Applying the concept of “similar management for similar risks,” guideline developers benchmarked risks to the risks associated with accepted screening and management strategies. Because the 5-year risk for CIN 3+ for a woman with an LSIL Pap finding is about 5.2%, and the recommendation for LSIL is colposcopy, 5.2% was set as the lower limit of the level of risk that provides enough benefit (detection of CIN 3+) to balance the potential harms of colposcopy.¹ (See the box on harms above.)

When women return to prolonged screening as follow-up to abnormal cytology or a positive HPV test, acceptable risk was considered to be that approximating the risk for CIN3+ three years after negative cytology or 5 years after negative cotesting—as these risks were considered acceptable to guide recent primary cervical screening guidelines.^2-4

To be as precise as possible, experts stratified the guidelines by risk, according to the woman’s age, cytologic diagnosis, and HPV status, including HPV genotyping for types 16 and 18, when tested. Of course, guidelines for management apply only to women who are found to have abnormalities during routine screening.¹ Women who experience postcoital or unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion need individualized evaluations.¹

Only changes or additions to the guidelines are listed here, so be sure to read the published guidelines and supplemental articles and/or visit the Web sites listed earlier for a review of all the guidelines.

What’s new in managing women with unsatisfactory Pap results?

In general, cytology should be repeated in 2 to 4 months.

If the unsatisfactory Pap test is part of a cotest, then the following strategies are appropriate:

• If the HPV test is positive, either repeating the Pap test or moving directly to colposcopy is acceptable
• If HPV genotyping was reported and is positive for type 16 or 18, colposcopy is indicated.

Colposcopy also is recommended when two consecutive Pap tests are unsatisfactory.

What’s new in managing women with normal cytology but no, or insufficient, endocervical cells/transformation-zone component?

The answer varies by age:

• For women 21 to 29 years – routine screening with cytology in 3 years is recommended
• For women 30 years and older:
  • When cotesting is done, the HPV result guides management:
    • HPV-negative: routine screening with cotesting in 5 years is preferred
    • HPV-positive: either cotesting in 1 year or immediate genotyping is recommended
  • If HPV testing was not done, then HPV testing is recommended, with management guided by results.

What’s new in managing women aged 21 to 24 with abnormal cervical cytology or CIN?

Young women of this age are at high risk for HPV infection but very low risk for cancer. Aggressive management usually involves more harm than benefit, promoting observation. Adolescents are no longer screened; management previously reserved for adolescents is now appropriate for women aged 21 to 24 years.

If the Pap result is:

• ASC-US or LSIL:
  • No colposcopy is needed. The Pap test should be repeated annually for 2 years, with colposcopy after 1 year only when the finding is HSIL and after 2 years if ASC-US or LSIL findings persist
  • HPV triage for ASC-US is not recommended, but if it is done:
    • HPV-negative women should continue routine screening with a Pap test in 3 years
    • HPV-positive women should have annual cytology for 2 years, with colposcopy after 1 year only if the result is HSIL and after 2 years if ASC-US or LSIL findings persist.

• ASC-H or HSIL:
  • Colposcopy is recommended, but immediate treatment (see-and-treat LEEP) is unacceptable
  • Women with no CIN 2 or CIN 3 at colposcopy should be followed with colposcopy and cytology every 6 months for as long as 2 years, until two consecutive Pap tests are negative and no high-grade colposcopic abnormality is observed
  • Repeat biopsies are indicated if cytology at 1 year is again ASC-H or HSIL
  • Diagnostic excision is recommended if HSIL cytology persists for 2 years.

Changes in the management of histologic findings

If CIN 1 is detected, management depends on the antecedent cytology report:

• If the prior Pap finding was ASC-US or LSIL, observation with annual cytology is recommended
• If the prior Pap finding was ASC-H or HSIL, observation for as long as 24 months is recommended, using both colposcopy and cytology at 6-month intervals, provided the colposcopic examination is adequate and endocervical assessment is negative.

If CIN 2 is detected, observation is preferred but treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 2/CIN 3 (not otherwise differentiated) is detected, either observation or treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 3 is detected in a woman of any age, treatment is indicated.

What’s new in managing women 30 years and older who have discordant cotest results?

Use cotesting management recommendations only for women 30 years and older.

If the finding is:

• HPV-positive/Pap-negative (HPV+/ Pap-), the two options are:
  • Repeat cotesting in 1 year, with colposcopy if the finding is again HPV+ or the Pap is ASC-US or more severe (including HPV-/ASC-US), and repeat cotesting in 3 years if results for both the HPV test and the Pap are negative (HPV-/Pap-)
  • Genotyping, with colposcopy if HPV 16 or 18 is identified and repeat cotesting in 1 year if both HPV 16 and 18 are negative
• HPV-/ASC-US:
  • Repeat the cotest in 3 years
• HPV-/LSIL, the options are:
  • Cotesting in 1 year (preferred)
  • Colposcopy (acceptable)
• HPV+/LSIL or LSIL/no HPV result:
  • Colposcopy
• HPV-/HSIL or HPV-/ASC-H:
  • Colposcopy
• HPV-/AGC
  • Colposcopy, often with endometrial sampling.

New terminology unifies all lower genital tract HPV intraepithelial neoplasia

Darragh TM, Colgan TJ, Cox JT, et al; LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16(3):205–242.

In 2012, the Lower Anogenital Squamous Terminology (LAST) standardization project created new histology terminology for HPV-related lesions of the lower genital tract. The LSIL finding was designated as the all-encompassing term for CIN 1, vaginal intraepithelial neoplasia 1 (VaIN 1), vulvar intraepithelial neoplasia 1 (VIN 1), penile intraepithelial neoplasia 1 (PeIN 1), perianal intraepithelial neoplasia 1 (PAIN 1) and anal intraepithelial neoplasia 1 (AIN 1). Intraepithelial neoplasia (IN) graded 2, 2/3, and 3 from each of these areas is designated HSIL.⁵

When CIN 2 and CIN 3 can be differentiated, these designations can be reported along with the HSIL diagnosis. However, after thoughtful deliberation, the delegates to the ASCCP consensus conference decided that there is not yet enough outcome data available to determine different management strategies when using the new LAST histopathology terminology. They recommended that, until evidence is available, results reported as histologic (not cytologic) LSIL should be managed as CIN 1, and histologic (not cytologic) HSIL should be managed as CIN 2/CIN 3.

We want to hear from you! Tell us what you think.

Dr. Einstein reports that Montefiore Medical Center has received payment from Roche and Hologic for time he spent as an advisor or educational speaker. In some cases, his travel has been paid for when required for meetings. In addition, Dr. Einstein reports that Montefiore has received grant funding from Roche, Hologic, and Becton-Dickinson for research-related costs of clinical trials that he has been the overall or Montefiore principal investigator.

Dr. Cox reports that he is a consultant to OncoHealth; a member of the Scientific Advisory Boards for Roche and Hologic; a speaker for Roche; and on the Data and Safety Monitoring Board for HPV vaccines for Merck.

Cervical cancer screening is necessarily complex, and guidelines must change fairly frequently as our understanding of the natural history of HPV infection and cervical cancer continues to evolve. Up-to-date guidelines enhance our ability to detect cervical intraepithelial neoplasia and cancer early and manage them appropriately.

In April 2013, the American Society for Colposcopy and Cervical Pathology (ASCCP) updated guidelines for the management of abnormal cervical cytology and cervical cancer precursors for the first time since 2006.¹ This update follows new cervical cancer screening guidelines published in 2012 by the ACS/ASCCP/ASCP,² the USPSTF,³ and the American College of Obstetricians and Gynecologists⁴ (and reported in OBG Management in June 2012⁵).

For many clinicians, all these modifications amount to a dizzying “sea change” in the way they have been screening and managing patients to prevent cervical cancer. Clinicians often express frustration with the guidelines, both for their complexity and for what seems like all-too-frequent changes. Do they really need to change … again? Do they really need to get even more complex? And what about them is really new?

This article addresses these questions by reviewing the guidelines and their updates in more depth. For a specific answer to the question of “What’s new?” see sidebar below.

Did the guidelines really need to change … again?

Cervical cancer screening tests—be they the Pap test or a human papillomavirus (HPV) test—are not as clear-cut as other tests used to screen for sexually transmitted infections or their effects. We treat a patient whenever her gonorrhea or Chlamydia test is positive, for example. However, other than cytology classified as high-grade (ie, HSIL), which may prompt immediate treatment in women 25 years and older by “see-and-treat” loop electrosurgical excision procedure (LEEP), neither cervical cytology nor HPV testing is sufficiently specific for present disease (cervical intraepithelial neoplasia [CIN] 3 or cancer) to warrant treatment without a diagnostic work-up. That’s because the cause of cervical cancer (infection with HPV) usually does not produce CIN 3 or cancer, and the cell changes that it does produce most often (atypia and koilocytosis) are very common. And other cervical-vaginal changes associated with hormonal fluctuations, tampons, intercourse, and so on, may result in cervical cytologic changes unrelated to HPV and, therefore, do not represent a risk for cervical cancer.

How can we best sort out who needs to be evaluated without under- or overdoing it? When we find CIN, some of which is destined to progress and some not, how do we reduce the risk of overtreatment without increasing the likelihood that some will progress to cancer? If we have treated CIN or adenocarcinoma in situ (AIS), how do we make sure there is no recurrence without risking over-management and potential overtreatment?

The first thing we do is ensure that we use our best clinical judgment and also respect the informed wishes of the patient. Because the guidelines are based on the best available data, and on expert opinion when data are lacking, guidelines developed through a consensus process provide a framework for care that is optimal for most women at each phase of their lives. This knowledge can help the clinician—and often the patient—make the best-informed decisions.

Do guidelines really need to get even more complex?

Consider the myriad management decisions that confront us in the field of cervical cancer screening, and the potential result of each choice. Even when cervical screening involves cytology alone, there are five major categories for abnormal results, each associated with a different level of risk requiring a unique level of management:

• atypical squamous cells – undetermined significance (ASC-US)
• atypical squamous cells – cannot rule out a high-grade lesion (ASC-H)
• atypical glandular cells (AGC)
• low-grade squamous intraepithelial lesion (LSIL)
• high-grade squamous intraepithelial lesion (HSIL).

Add in HPV testing with cervical cytology for women 30 years and older, and there is one more abnormal category—normal Pap/ HPV-positive. And these categories just cover initial management. Also needed are guidelines for appropriate follow-up of women who undergo colposcopy for each abnormal cytologic result when no CIN 2, CIN 3, or AIS is found that requires treatment, as well as guidelines for managing women following treatment when high-grade histology is found.

As our understanding of the natural history of HPV and cervical oncogenesis has increased, it has become clearer that we must further adjust management decisions on the basis of age, essentially creating many parallel sets of guidelines for women aged 21 to 24, 25 to 29, and 30 years and older.

Yes, cervical screening and management are complex. We are fortunate that the Internet and new “apps” for smartphones give us easy access to guidelines for most of the potential combinations of clinical findings and results. The guideline algorithms are available at www.asccp.org, and full explanatory articles are available at www.jlgtd.com and www.greenjournal.org (comprehensive apps are available for download for almost every smartphone device).

Remember, it is impossible to create guidelines for every possible clinical situation, so clinical judgment must always be paramount when applying guidelines to individual patients.¹

What are the major changes of the latest set of guidelines and its update?

Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–846. [Also published in J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.]

Let’s start by focusing on how the experts crafted the 2012 guidelines. New evidence to guide decisions about the management of abnormal screening tests, CIN, and AIS emerged in 2012 from a review of the world literature and from analyses of a large 7-year clinical database (1.4 million women) at the Kaiser Permanente Northern California Medical Care Plan, conducted in collaboration with scientists from the National Cancer Institute.¹

Most of the 2006 guidelines remain valid, but new evidence has modified some of the guidelines and created others where gaps existed. Guideline developers recognized that cervical cancer prevention is a process that entails both benefits and potential harms, and that the potential risks cannot be reduced to zero with the strategies currently available. Attempts to achieve zero risk could result in unbalanced harms, including overtreatment.

Defining acceptable risk levels

Applying the concept of “similar management for similar risks,” guideline developers benchmarked risks to the risks associated with accepted screening and management strategies. Because the 5-year risk for CIN 3+ for a woman with an LSIL Pap finding is about 5.2%, and the recommendation for LSIL is colposcopy, 5.2% was set as the lower limit of the level of risk that provides enough benefit (detection of CIN 3+) to balance the potential harms of colposcopy.¹ (See the box on harms above.)

When women return to prolonged screening as follow-up to abnormal cytology or a positive HPV test, acceptable risk was considered to be that approximating the risk for CIN3+ three years after negative cytology or 5 years after negative cotesting—as these risks were considered acceptable to guide recent primary cervical screening guidelines.^2-4

To be as precise as possible, experts stratified the guidelines by risk, according to the woman’s age, cytologic diagnosis, and HPV status, including HPV genotyping for types 16 and 18, when tested. Of course, guidelines for management apply only to women who are found to have abnormalities during routine screening.¹ Women who experience postcoital or unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion need individualized evaluations.¹

Only changes or additions to the guidelines are listed here, so be sure to read the published guidelines and supplemental articles and/or visit the Web sites listed earlier for a review of all the guidelines.

What’s new in managing women with unsatisfactory Pap results?

In general, cytology should be repeated in 2 to 4 months.

If the unsatisfactory Pap test is part of a cotest, then the following strategies are appropriate:

• If the HPV test is positive, either repeating the Pap test or moving directly to colposcopy is acceptable
• If HPV genotyping was reported and is positive for type 16 or 18, colposcopy is indicated.

Colposcopy also is recommended when two consecutive Pap tests are unsatisfactory.

What’s new in managing women with normal cytology but no, or insufficient, endocervical cells/transformation-zone component?

The answer varies by age:

• For women 21 to 29 years – routine screening with cytology in 3 years is recommended
• For women 30 years and older:
  • When cotesting is done, the HPV result guides management:
    • HPV-negative: routine screening with cotesting in 5 years is preferred
    • HPV-positive: either cotesting in 1 year or immediate genotyping is recommended
  • If HPV testing was not done, then HPV testing is recommended, with management guided by results.

What’s new in managing women aged 21 to 24 with abnormal cervical cytology or CIN?

Young women of this age are at high risk for HPV infection but very low risk for cancer. Aggressive management usually involves more harm than benefit, promoting observation. Adolescents are no longer screened; management previously reserved for adolescents is now appropriate for women aged 21 to 24 years.

If the Pap result is:

• ASC-US or LSIL:
  • No colposcopy is needed. The Pap test should be repeated annually for 2 years, with colposcopy after 1 year only when the finding is HSIL and after 2 years if ASC-US or LSIL findings persist
  • HPV triage for ASC-US is not recommended, but if it is done:
    • HPV-negative women should continue routine screening with a Pap test in 3 years
    • HPV-positive women should have annual cytology for 2 years, with colposcopy after 1 year only if the result is HSIL and after 2 years if ASC-US or LSIL findings persist.

• ASC-H or HSIL:
  • Colposcopy is recommended, but immediate treatment (see-and-treat LEEP) is unacceptable
  • Women with no CIN 2 or CIN 3 at colposcopy should be followed with colposcopy and cytology every 6 months for as long as 2 years, until two consecutive Pap tests are negative and no high-grade colposcopic abnormality is observed
  • Repeat biopsies are indicated if cytology at 1 year is again ASC-H or HSIL
  • Diagnostic excision is recommended if HSIL cytology persists for 2 years.

Changes in the management of histologic findings

If CIN 1 is detected, management depends on the antecedent cytology report:

• If the prior Pap finding was ASC-US or LSIL, observation with annual cytology is recommended
• If the prior Pap finding was ASC-H or HSIL, observation for as long as 24 months is recommended, using both colposcopy and cytology at 6-month intervals, provided the colposcopic examination is adequate and endocervical assessment is negative.

If CIN 2 is detected, observation is preferred but treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 2/CIN 3 (not otherwise differentiated) is detected, either observation or treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 3 is detected in a woman of any age, treatment is indicated.

What’s new in managing women 30 years and older who have discordant cotest results?

Use cotesting management recommendations only for women 30 years and older.

If the finding is:

• HPV-positive/Pap-negative (HPV+/ Pap-), the two options are:
  • Repeat cotesting in 1 year, with colposcopy if the finding is again HPV+ or the Pap is ASC-US or more severe (including HPV-/ASC-US), and repeat cotesting in 3 years if results for both the HPV test and the Pap are negative (HPV-/Pap-)
  • Genotyping, with colposcopy if HPV 16 or 18 is identified and repeat cotesting in 1 year if both HPV 16 and 18 are negative
• HPV-/ASC-US:
  • Repeat the cotest in 3 years
• HPV-/LSIL, the options are:
  • Cotesting in 1 year (preferred)
  • Colposcopy (acceptable)
• HPV+/LSIL or LSIL/no HPV result:
  • Colposcopy
• HPV-/HSIL or HPV-/ASC-H:
  • Colposcopy
• HPV-/AGC
  • Colposcopy, often with endometrial sampling.

New terminology unifies all lower genital tract HPV intraepithelial neoplasia

Darragh TM, Colgan TJ, Cox JT, et al; LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16(3):205–242.

In 2012, the Lower Anogenital Squamous Terminology (LAST) standardization project created new histology terminology for HPV-related lesions of the lower genital tract. The LSIL finding was designated as the all-encompassing term for CIN 1, vaginal intraepithelial neoplasia 1 (VaIN 1), vulvar intraepithelial neoplasia 1 (VIN 1), penile intraepithelial neoplasia 1 (PeIN 1), perianal intraepithelial neoplasia 1 (PAIN 1) and anal intraepithelial neoplasia 1 (AIN 1). Intraepithelial neoplasia (IN) graded 2, 2/3, and 3 from each of these areas is designated HSIL.⁵

When CIN 2 and CIN 3 can be differentiated, these designations can be reported along with the HSIL diagnosis. However, after thoughtful deliberation, the delegates to the ASCCP consensus conference decided that there is not yet enough outcome data available to determine different management strategies when using the new LAST histopathology terminology. They recommended that, until evidence is available, results reported as histologic (not cytologic) LSIL should be managed as CIN 1, and histologic (not cytologic) HSIL should be managed as CIN 2/CIN 3.

We want to hear from you! Tell us what you think.

Dr. Einstein reports that Montefiore Medical Center has received payment from Roche and Hologic for time he spent as an advisor or educational speaker. In some cases, his travel has been paid for when required for meetings. In addition, Dr. Einstein reports that Montefiore has received grant funding from Roche, Hologic, and Becton-Dickinson for research-related costs of clinical trials that he has been the overall or Montefiore principal investigator.

Dr. Cox reports that he is a consultant to OncoHealth; a member of the Scientific Advisory Boards for Roche and Hologic; a speaker for Roche; and on the Data and Safety Monitoring Board for HPV vaccines for Merck.

Cervical cancer screening is necessarily complex, and guidelines must change fairly frequently as our understanding of the natural history of HPV infection and cervical cancer continues to evolve. Up-to-date guidelines enhance our ability to detect cervical intraepithelial neoplasia and cancer early and manage them appropriately.

In April 2013, the American Society for Colposcopy and Cervical Pathology (ASCCP) updated guidelines for the management of abnormal cervical cytology and cervical cancer precursors for the first time since 2006.¹ This update follows new cervical cancer screening guidelines published in 2012 by the ACS/ASCCP/ASCP,² the USPSTF,³ and the American College of Obstetricians and Gynecologists⁴ (and reported in OBG Management in June 2012⁵).

For many clinicians, all these modifications amount to a dizzying “sea change” in the way they have been screening and managing patients to prevent cervical cancer. Clinicians often express frustration with the guidelines, both for their complexity and for what seems like all-too-frequent changes. Do they really need to change … again? Do they really need to get even more complex? And what about them is really new?

This article addresses these questions by reviewing the guidelines and their updates in more depth. For a specific answer to the question of “What’s new?” see sidebar below.

Did the guidelines really need to change … again?

Cervical cancer screening tests—be they the Pap test or a human papillomavirus (HPV) test—are not as clear-cut as other tests used to screen for sexually transmitted infections or their effects. We treat a patient whenever her gonorrhea or Chlamydia test is positive, for example. However, other than cytology classified as high-grade (ie, HSIL), which may prompt immediate treatment in women 25 years and older by “see-and-treat” loop electrosurgical excision procedure (LEEP), neither cervical cytology nor HPV testing is sufficiently specific for present disease (cervical intraepithelial neoplasia [CIN] 3 or cancer) to warrant treatment without a diagnostic work-up. That’s because the cause of cervical cancer (infection with HPV) usually does not produce CIN 3 or cancer, and the cell changes that it does produce most often (atypia and koilocytosis) are very common. And other cervical-vaginal changes associated with hormonal fluctuations, tampons, intercourse, and so on, may result in cervical cytologic changes unrelated to HPV and, therefore, do not represent a risk for cervical cancer.

How can we best sort out who needs to be evaluated without under- or overdoing it? When we find CIN, some of which is destined to progress and some not, how do we reduce the risk of overtreatment without increasing the likelihood that some will progress to cancer? If we have treated CIN or adenocarcinoma in situ (AIS), how do we make sure there is no recurrence without risking over-management and potential overtreatment?

The first thing we do is ensure that we use our best clinical judgment and also respect the informed wishes of the patient. Because the guidelines are based on the best available data, and on expert opinion when data are lacking, guidelines developed through a consensus process provide a framework for care that is optimal for most women at each phase of their lives. This knowledge can help the clinician—and often the patient—make the best-informed decisions.

Do guidelines really need to get even more complex?

Consider the myriad management decisions that confront us in the field of cervical cancer screening, and the potential result of each choice. Even when cervical screening involves cytology alone, there are five major categories for abnormal results, each associated with a different level of risk requiring a unique level of management:

• atypical squamous cells – undetermined significance (ASC-US)
• atypical squamous cells – cannot rule out a high-grade lesion (ASC-H)
• atypical glandular cells (AGC)
• low-grade squamous intraepithelial lesion (LSIL)
• high-grade squamous intraepithelial lesion (HSIL).

Add in HPV testing with cervical cytology for women 30 years and older, and there is one more abnormal category—normal Pap/ HPV-positive. And these categories just cover initial management. Also needed are guidelines for appropriate follow-up of women who undergo colposcopy for each abnormal cytologic result when no CIN 2, CIN 3, or AIS is found that requires treatment, as well as guidelines for managing women following treatment when high-grade histology is found.

As our understanding of the natural history of HPV and cervical oncogenesis has increased, it has become clearer that we must further adjust management decisions on the basis of age, essentially creating many parallel sets of guidelines for women aged 21 to 24, 25 to 29, and 30 years and older.

Yes, cervical screening and management are complex. We are fortunate that the Internet and new “apps” for smartphones give us easy access to guidelines for most of the potential combinations of clinical findings and results. The guideline algorithms are available at www.asccp.org, and full explanatory articles are available at www.jlgtd.com and www.greenjournal.org (comprehensive apps are available for download for almost every smartphone device).

Remember, it is impossible to create guidelines for every possible clinical situation, so clinical judgment must always be paramount when applying guidelines to individual patients.¹

What are the major changes of the latest set of guidelines and its update?

Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):829–846. [Also published in J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.]

Let’s start by focusing on how the experts crafted the 2012 guidelines. New evidence to guide decisions about the management of abnormal screening tests, CIN, and AIS emerged in 2012 from a review of the world literature and from analyses of a large 7-year clinical database (1.4 million women) at the Kaiser Permanente Northern California Medical Care Plan, conducted in collaboration with scientists from the National Cancer Institute.¹

Most of the 2006 guidelines remain valid, but new evidence has modified some of the guidelines and created others where gaps existed. Guideline developers recognized that cervical cancer prevention is a process that entails both benefits and potential harms, and that the potential risks cannot be reduced to zero with the strategies currently available. Attempts to achieve zero risk could result in unbalanced harms, including overtreatment.

Defining acceptable risk levels

Applying the concept of “similar management for similar risks,” guideline developers benchmarked risks to the risks associated with accepted screening and management strategies. Because the 5-year risk for CIN 3+ for a woman with an LSIL Pap finding is about 5.2%, and the recommendation for LSIL is colposcopy, 5.2% was set as the lower limit of the level of risk that provides enough benefit (detection of CIN 3+) to balance the potential harms of colposcopy.¹ (See the box on harms above.)

When women return to prolonged screening as follow-up to abnormal cytology or a positive HPV test, acceptable risk was considered to be that approximating the risk for CIN3+ three years after negative cytology or 5 years after negative cotesting—as these risks were considered acceptable to guide recent primary cervical screening guidelines.^2-4

To be as precise as possible, experts stratified the guidelines by risk, according to the woman’s age, cytologic diagnosis, and HPV status, including HPV genotyping for types 16 and 18, when tested. Of course, guidelines for management apply only to women who are found to have abnormalities during routine screening.¹ Women who experience postcoital or unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion need individualized evaluations.¹

Only changes or additions to the guidelines are listed here, so be sure to read the published guidelines and supplemental articles and/or visit the Web sites listed earlier for a review of all the guidelines.

What’s new in managing women with unsatisfactory Pap results?

In general, cytology should be repeated in 2 to 4 months.

If the unsatisfactory Pap test is part of a cotest, then the following strategies are appropriate:

• If the HPV test is positive, either repeating the Pap test or moving directly to colposcopy is acceptable
• If HPV genotyping was reported and is positive for type 16 or 18, colposcopy is indicated.

Colposcopy also is recommended when two consecutive Pap tests are unsatisfactory.

What’s new in managing women with normal cytology but no, or insufficient, endocervical cells/transformation-zone component?

The answer varies by age:

• For women 21 to 29 years – routine screening with cytology in 3 years is recommended
• For women 30 years and older:
  • When cotesting is done, the HPV result guides management:
    • HPV-negative: routine screening with cotesting in 5 years is preferred
    • HPV-positive: either cotesting in 1 year or immediate genotyping is recommended
  • If HPV testing was not done, then HPV testing is recommended, with management guided by results.

What’s new in managing women aged 21 to 24 with abnormal cervical cytology or CIN?

Young women of this age are at high risk for HPV infection but very low risk for cancer. Aggressive management usually involves more harm than benefit, promoting observation. Adolescents are no longer screened; management previously reserved for adolescents is now appropriate for women aged 21 to 24 years.

If the Pap result is:

• ASC-US or LSIL:
  • No colposcopy is needed. The Pap test should be repeated annually for 2 years, with colposcopy after 1 year only when the finding is HSIL and after 2 years if ASC-US or LSIL findings persist
  • HPV triage for ASC-US is not recommended, but if it is done:
    • HPV-negative women should continue routine screening with a Pap test in 3 years
    • HPV-positive women should have annual cytology for 2 years, with colposcopy after 1 year only if the result is HSIL and after 2 years if ASC-US or LSIL findings persist.

• ASC-H or HSIL:
  • Colposcopy is recommended, but immediate treatment (see-and-treat LEEP) is unacceptable
  • Women with no CIN 2 or CIN 3 at colposcopy should be followed with colposcopy and cytology every 6 months for as long as 2 years, until two consecutive Pap tests are negative and no high-grade colposcopic abnormality is observed
  • Repeat biopsies are indicated if cytology at 1 year is again ASC-H or HSIL
  • Diagnostic excision is recommended if HSIL cytology persists for 2 years.

Changes in the management of histologic findings

If CIN 1 is detected, management depends on the antecedent cytology report:

• If the prior Pap finding was ASC-US or LSIL, observation with annual cytology is recommended
• If the prior Pap finding was ASC-H or HSIL, observation for as long as 24 months is recommended, using both colposcopy and cytology at 6-month intervals, provided the colposcopic examination is adequate and endocervical assessment is negative.

If CIN 2 is detected, observation is preferred but treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 2/CIN 3 (not otherwise differentiated) is detected, either observation or treatment is acceptable (see the guidelines for detailed recommendations).

If CIN 3 is detected in a woman of any age, treatment is indicated.

What’s new in managing women 30 years and older who have discordant cotest results?

Use cotesting management recommendations only for women 30 years and older.

If the finding is:

• HPV-positive/Pap-negative (HPV+/ Pap-), the two options are:
  • Repeat cotesting in 1 year, with colposcopy if the finding is again HPV+ or the Pap is ASC-US or more severe (including HPV-/ASC-US), and repeat cotesting in 3 years if results for both the HPV test and the Pap are negative (HPV-/Pap-)
  • Genotyping, with colposcopy if HPV 16 or 18 is identified and repeat cotesting in 1 year if both HPV 16 and 18 are negative
• HPV-/ASC-US:
  • Repeat the cotest in 3 years
• HPV-/LSIL, the options are:
  • Cotesting in 1 year (preferred)
  • Colposcopy (acceptable)
• HPV+/LSIL or LSIL/no HPV result:
  • Colposcopy
• HPV-/HSIL or HPV-/ASC-H:
  • Colposcopy
• HPV-/AGC
  • Colposcopy, often with endometrial sampling.

New terminology unifies all lower genital tract HPV intraepithelial neoplasia

Darragh TM, Colgan TJ, Cox JT, et al; LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16(3):205–242.

In 2012, the Lower Anogenital Squamous Terminology (LAST) standardization project created new histology terminology for HPV-related lesions of the lower genital tract. The LSIL finding was designated as the all-encompassing term for CIN 1, vaginal intraepithelial neoplasia 1 (VaIN 1), vulvar intraepithelial neoplasia 1 (VIN 1), penile intraepithelial neoplasia 1 (PeIN 1), perianal intraepithelial neoplasia 1 (PAIN 1) and anal intraepithelial neoplasia 1 (AIN 1). Intraepithelial neoplasia (IN) graded 2, 2/3, and 3 from each of these areas is designated HSIL.⁵

When CIN 2 and CIN 3 can be differentiated, these designations can be reported along with the HSIL diagnosis. However, after thoughtful deliberation, the delegates to the ASCCP consensus conference decided that there is not yet enough outcome data available to determine different management strategies when using the new LAST histopathology terminology. They recommended that, until evidence is available, results reported as histologic (not cytologic) LSIL should be managed as CIN 1, and histologic (not cytologic) HSIL should be managed as CIN 2/CIN 3.

We want to hear from you! Tell us what you think.

Dr. Cox is a consultant to Gen-Probe, OncoHealth, and Roche, and serves on the Data and Safety Monitoring Committee (DSMB) for Merck HPV vaccine trials. He is a speaker for Bradley Pharmaceuticals.

The American Cancer Society estimates that approximately 12,700 new cases of invasive cervical cancer were diagnosed in 2011 in the United States; nearly 4,300 of those women will die of the disease, the Society projects.¹ Great disparities in prevalence and incidence persist, with the rate of cervical cancer 1) highest in Latino women and 2) about 50% higher in African-American women than in non-Latino white women.

Because approximately 60% of cervical cancers occur in women who don’t undergo any screening for the disease, or who undergo only very infrequent screening, bringing more women in to be screened is most important. For women who are screened very infrequently, providing testing with the longest interval that provides safety should also reduce their risk of cancer.

Two advances have the potential to provide huge benefit in reducing the risk of cervical cancer: 1) increasing utilization of human papillomavirus (HPV) testing with Pap testing (so-called co-testing) for screening women 30 years and older and 2) widespread administration of the HPV vaccine to girls before they begin sexual activity. Regrettably, the promise of the HPV vaccine has not yet been fulfilled: Vaccine uptake (all three doses) among the primary target population hasn’t even reached 40%. And co-testing continues to be underutilized—in part because the best management strategy for women who have a negative Pap test result but a positive HPV test result (written here as “Pap–/HPV+”) has been less than clear.

Disappointments aside, 2011 did bring us a wealth of data on 1) the likely value of co-testing in preventing cervical cancer, and 2) improved management strategies for Pap–/HPV+ women—the areas of practice that I’ve made the focus of this year’s Update. The first question to ask: Does co-testing reduce the risk of cervical cancer more than current screening strategies that employ the Pap test?

Primary cytology (Pap test) screening (above) augmented by HPV testing—so-called co-testing—appears to cut the long-term risk of cervical Ca. Consider making a co-testing stratagem part of your practice, urges author Dr. J. Thomas Cox.

Will co-testing reduce the rate of cervical Ca to a greater degree than Pap screening has?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13(1):78–88.

Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7):663–672.

Recent studies have brought us closer to answering this question—and data certainly appear to suggest that the answer is “Yes.” Evidence from randomized controlled trials, prospective long-term cohort trials, and a large US screening population show that introducing HPV testing into cervical cancer screening could reduce cervical cancer incidence in women age ≥30—and even cervical cancer mortality.

I discussed one of these trials—the Italian NTCC trial—in the 2011 OBG Management Update on Cervical Disease [read that article in the archive at www.obgmanagement.com]; earlier detection and treatment of cervical intraepithelial neoplasia grade-3 (CIN 3) lesions in the first screening round in the co-tested group were proposed as the reasons that no cancers were detected in the second screening round (nine cancers were detected in the women having cytology only).²

Similar results were reported in the POBASCAM study from the Netherlands, in which more than 44,000 women were randomized to co-testing or screening with cytology alone, then re-screened 5 years later. As in the NTCC trial, more cases of CIN 3+ were detected and treated at the initial screen by co-testing than by cytology alone (i.e., projected out to 79 additional cases of CIN 3 and 30 additional cancers for every 100,000 women screened), with fewer cases of CIN 3+ detected in the co-tested group in the subsequent 5 years than in the cytology-only group (again, projected out to 24 fewer cases of CIN 3 and 10 fewer cancers for every 100,000 women).

(In a review of these study findings, experts at the National Cancer Institute [NCI] estimated that co-testing in POBASCAM reduced the risk of cervical cancer to only 2.2 cancers for every 100,000 women a year—demonstrating the safety of a 5-year screening interval.³) This means that women testing Pap–/HPV–, who are best screened at 3-year intervals, would be safe with an interval as long as 5 years—providing greater protection for irregularly screened women.

FIGURE 1 Cervical adenocarcinoma in situ

Cervical AIS demonstrated in a cytology specimen. Most studies have shown that cytology is less sensitive than HPV testing for a glandular lesion.
Photo: Courtesy of Dennis O’Conner, MD.

Similar results were described by Katki and coworkers in a large HMO screening population in the United States, in which Pap–/HPV+ women had half the risk of cancer over the subsequent 5 years, compared with women who were negative by Pap testing only (3.2 cases for every 100,000 women, compared with 7.5 cases, respectively). Of the total cases of CIN 3+ found, 35% of cases of CIN 3 and adenocarcinoma in situ (AIS) (FIGURE 1) were detected in women Pap-/HPV+, as were 29% of cancers. Cytology has been shown, in almost all studies, to be less sensitive for glandular lesions; it isn’t surprising, therefore, that 63% of adenocarcinomas found in this study population were detected by HPV testing only.

These results appear to provide overwhelming evidence of the benefit of including HPV testing in screening programs for cervical cancer.³

Dilemma: How do we best manage women who are Pap–/HPV+?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Although co-testing appears to reduce the risk of cervical cancer—allowing a safer margin for Pap-negative plus HPV-negative (Pap–/HPV–) women if they miss by up to 2 years their 3-year recommended screening—the question remains: What is the best way to manage Pap–/HPV+ women?

The primary recommendation by both the American Society for Colposcopy and Cervical Pathology (ASCCP) and ACOG is to re-screen them in 12 months, rather than send them immediately for colposcopy. Why? Because HPV infection 1) is relatively common among women who do not have CIN 2, 3 or invasive cervical cancer and 2) most often resolves without causing significant disease.

But re-screening these patients in 12 months negates much of the benefit of the high clinical sensitivity of HPV testing because it could lead to significant delay in the diagnosis and treatment of some women who already have either cervical cancer or advanced CIN 3 that might progress to cancer before their next evaluation. This concern is supported by the findings of the studies I discussed earlier.^1-3

Although cervical cancer missed at cytology screening is uncommon, 44 cervical cancers were reported by Kinney and coworkers in a large screening population in women who had one or more Pap–/HPV+ co-test results (18 had two or more Pap–/HPV+ results before diagnosis). More than 60% had cervical adenocarcinoma, which is more than three times the normal proportion of glandular cancer to squamous cervical cancer—again highlighting the relative insensitivity of cytology to detect glandular lesions.

Other drawbacks of waiting 12 months for further evaluation include 1) prolonged uncertainty for the patient and 2) the potential for losing her to follow-up, which occurs in as many as 50% of subjects in many studies.

Therefore, finding patients who are at greatest risk of CIN 2+ among the larger group of Pap–/HPV+ women, and referring them immediately for colposcopy, should provide great benefit.

Note that the 2006 ASCCP guidelines included a statement that, once an FDA-approved test for HPV 16, 18 was available, triage of Pap–/HPV+ patients who are positive for HPV 16, 18 could identify a majority at greatest risk of CIN 2,3+ and who would therefore benefit most by referral for colposcopy. In contrast, patients at lower risk (i.e., positive for any of the other 12 HPV types but not for types 16 and 18) would be better managed by repeating co-testing in 12 months—referring for colposcopy only those who are found again to be HPV+ or who have an abnormal Pap test.

In the next section of this Update, I explore recent evidence about the important role played by HPV 16, 18 in cervical carcinogenesis.

HPV 16, 18 pose long-term risk for CIN 3+ and cervical Ca

Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–1488.

The most compelling prediction of the risk of CIN 3+ in cases of either single (incident) or persistent high-risk HPV detection comes from a 13-year follow-up study out of Denmark. More than 8,600 Danish women, 20 to 29 years old at enrollment, were tested twice, 2 years apart, for HPV by the Hybrid Capture 2 High-Risk (HC2 HR) HPV DNA Test (Qiagen) and by line-blot assays for type-specific HPV.

Subjects were followed subsequently with routine screening; data on their overall long-term risk of CIN 3+ was obtained from the national Danish Pathology Data Bank. Among those who tested positive for HPV 16, absolute risk of CIN 3+ within 12 years of incident detection was 26.7%; for HPV 18, it was 19.1%—both percentages markedly higher than the 6% risk for women who tested positive for a panel of 10 other high-risk HPV types (also not including HPV 31, 33).

FIGURE 2 Over time, risk of CIN 3+ rises in all subpopulations infected by high-risk HPV

Shown is the absolute risk for CIN 3+ during follow-up among women who have HPV 16 persistence (red line), Hybrid Capture 2 High-Risk HPV DNA Test (HC2 HR) persistence for a panel of 13 high-risk HPV types (blue), incident or newly detected HPV 16 infection (i.e., HPV 16-negative at first examination and HPV 16-positive at second examination) (pink), and women with an incident high-risk HPV infection (i.e., negative for high-risk HPV by HC2 HR at first examination and positive at second examination) (green). For comparison, the dashed purple line shows the nearly flat absolute risk of CIN 3+ for women who are negative for high-risk HPV by HC2 HR at both examinations.
Source: Kjaer et al, 2010. Reproduced by permission of the publisher, Oxford University Press.

Risk associated with HPV 16. The most successfully persistent viral type was 16; just under 30% of subjects who were HPV 16+ on the first test remained HPV 16+ on the second test 2 years later. For this 30% subset, the risk of CIN 3+ was 8.9% at 3 years; 23.8% at 5 years; and an astonishing 47.4% at 12 years (FIGURE 2). In other words, almost half of subjects who had persistent HPV 16 in their 20s developed CIN 3 or cancer within 12 years. In contrast, the absolute risk for developing CIN 3+ within 12 years of a single negative HPV test was only 3%.

HPV 18. Viral type 18 was nearly as likely to persist as HPV 16; when persistent, it resulted in CIN 3+ in just under 30% of subjects within 12 years and tended to result in CIN 3+ that was detected later.

Using HPV 16, 18 testing to improve the management of Pap–/HPV+ women

Two more HPV tests are now FDA-approved for clinical use

In the 2006 Update on Cervical Disease [available in the archive at www.obgmanagement.com], I noted the importance of HPV 16, 18 in cervical carcinogenesis and observed that a test for these two viral types was on the horizon. It wasn’t until 2009 approval of the Cervista HPV DNA HR Test (Hologic), however, that such a test became available.

In 2011, two more tests were approved:

• cobas 4800 HPV DNA
• Aptima mRNA HPV.

Like Cervista, the cobas 4800 (Roche) is FDA-approved to detect HPV DNA types 16 and 18 individually; Gen-Probe’s Aptima HPV test is the first HPV E6,E7 mRNA test approved in the US; the company plans to add an HPV 16, 18 mRNA test. The addition of one, perhaps two, new HPV 16, 18 genotyping tests expands the opportunity for you to improve the management of Pap–/HPV+ patients.

Let’s look at new data that support testing of Pap–/HPV+ women for HPV 16, 18.

Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL; ATHENA (Addressing THE Need for Advanced HPV Diagnostics) Study Group. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4):578–586.

Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol. 2011;12(9):880–890.

Data to support the application to the FDA for approval of the cobas 4800 was provided by the ATHENA Trial, the largest (47,208 women) cervical screening trial of US women to assess the performance of HPV DNA testing with individual genotyping for HPV 16, 18, compared with the Pap.

Wright and co-workers. These investigators evaluated the subset of 32,260 women 30 years and older who had negative cytology. The overall prevalence of Pap–/HPV+ was 6.7%. Just over one quarter of the Pap–/HPV+ women (1.5% of the subset population) were positive for HPV 16 or 18, or both.

As has been shown in other studies, the overall prevalence of HPV declined with age, as did the prevalence of HPV 16, 18. The estimated absolute risk of CIN 3+ at colposcopy for women who were Pap–/HPV+ was only 4.1%, but their relative risk—that is, compared with women in whom both tests were negative—was 14.4%. The absolute risk for CIN 3+ increased to 9.8% for Pap-negative women who tested positive for HPV 16 or 18, or both, and to 11.7% in women who tested positive for HPV 16 only.

Ongoing work by Castle and colleagues. In a seminal 2007 article on risk management, Castle and colleagues proposed that women who had an absolute risk of CIN 3+ of ≥10% across 2–3 years of follow-up should have colposcopy.⁴ These data, therefore, clearly support the recommendation of ASCCP that Pap–/HPV 16+ and (or) HPV 18+ women should be referred for colposcopy (FIGURE 3).

FIGURE 3 Managing risk of CIN 3+ across 2 years of follow-up

This stratagem is based on 2006 ASCCP Consensus Guidelines, 2010 ACOG guidelines, and Castle and colleagues’ proposal in their 2007 article, “Risk assessment to guide the prevention of cervical cancer.”⁴
Figure courtesy of Thomas C. Wright, MD.

Now, in another review of the ATHENA results, expanded to a subset of women 25 years and older, Castle and co-workers reported that triage of Pap–/HPV+ women by testing for HPV 16, 18 detected 72% of all CIN 3+ that was missed by cytology alone. Because only 18% of Pap–/HPV+ women were positive for HPV 16, 18, the majority (i.e., 82% who were ≥25 years and 78% who were ≥30 years) could be reassured that their risk was sufficiently low that it could be best managed by repeating co-testing in 1 year. This avoids delaying the diagnosis of nearly three quarters of the Pap–/HPV+ women who have CIN 3+, without overburdening colposcopy services.

The ATHENA trial is ongoing; eventually, results from 3 years of follow-up of these women will be evaluated. The findings should add important information about the total burden of cervical precancer detected over a longer period after a Pap–/HPV+ result, with or without testing positive for HPV 16, 18.

We want to hear from you! Tell us what you think.

Dr. Cox is a consultant to Gen-Probe, OncoHealth, and Roche, and serves on the Data and Safety Monitoring Committee (DSMB) for Merck HPV vaccine trials. He is a speaker for Bradley Pharmaceuticals.

The American Cancer Society estimates that approximately 12,700 new cases of invasive cervical cancer were diagnosed in 2011 in the United States; nearly 4,300 of those women will die of the disease, the Society projects.¹ Great disparities in prevalence and incidence persist, with the rate of cervical cancer 1) highest in Latino women and 2) about 50% higher in African-American women than in non-Latino white women.

Because approximately 60% of cervical cancers occur in women who don’t undergo any screening for the disease, or who undergo only very infrequent screening, bringing more women in to be screened is most important. For women who are screened very infrequently, providing testing with the longest interval that provides safety should also reduce their risk of cancer.

Two advances have the potential to provide huge benefit in reducing the risk of cervical cancer: 1) increasing utilization of human papillomavirus (HPV) testing with Pap testing (so-called co-testing) for screening women 30 years and older and 2) widespread administration of the HPV vaccine to girls before they begin sexual activity. Regrettably, the promise of the HPV vaccine has not yet been fulfilled: Vaccine uptake (all three doses) among the primary target population hasn’t even reached 40%. And co-testing continues to be underutilized—in part because the best management strategy for women who have a negative Pap test result but a positive HPV test result (written here as “Pap–/HPV+”) has been less than clear.

Disappointments aside, 2011 did bring us a wealth of data on 1) the likely value of co-testing in preventing cervical cancer, and 2) improved management strategies for Pap–/HPV+ women—the areas of practice that I’ve made the focus of this year’s Update. The first question to ask: Does co-testing reduce the risk of cervical cancer more than current screening strategies that employ the Pap test?

Primary cytology (Pap test) screening (above) augmented by HPV testing—so-called co-testing—appears to cut the long-term risk of cervical Ca. Consider making a co-testing stratagem part of your practice, urges author Dr. J. Thomas Cox.

Will co-testing reduce the rate of cervical Ca to a greater degree than Pap screening has?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13(1):78–88.

Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7):663–672.

Recent studies have brought us closer to answering this question—and data certainly appear to suggest that the answer is “Yes.” Evidence from randomized controlled trials, prospective long-term cohort trials, and a large US screening population show that introducing HPV testing into cervical cancer screening could reduce cervical cancer incidence in women age ≥30—and even cervical cancer mortality.

I discussed one of these trials—the Italian NTCC trial—in the 2011 OBG Management Update on Cervical Disease [read that article in the archive at www.obgmanagement.com]; earlier detection and treatment of cervical intraepithelial neoplasia grade-3 (CIN 3) lesions in the first screening round in the co-tested group were proposed as the reasons that no cancers were detected in the second screening round (nine cancers were detected in the women having cytology only).²

Similar results were reported in the POBASCAM study from the Netherlands, in which more than 44,000 women were randomized to co-testing or screening with cytology alone, then re-screened 5 years later. As in the NTCC trial, more cases of CIN 3+ were detected and treated at the initial screen by co-testing than by cytology alone (i.e., projected out to 79 additional cases of CIN 3 and 30 additional cancers for every 100,000 women screened), with fewer cases of CIN 3+ detected in the co-tested group in the subsequent 5 years than in the cytology-only group (again, projected out to 24 fewer cases of CIN 3 and 10 fewer cancers for every 100,000 women).

(In a review of these study findings, experts at the National Cancer Institute [NCI] estimated that co-testing in POBASCAM reduced the risk of cervical cancer to only 2.2 cancers for every 100,000 women a year—demonstrating the safety of a 5-year screening interval.³) This means that women testing Pap–/HPV–, who are best screened at 3-year intervals, would be safe with an interval as long as 5 years—providing greater protection for irregularly screened women.

FIGURE 1 Cervical adenocarcinoma in situ

Cervical AIS demonstrated in a cytology specimen. Most studies have shown that cytology is less sensitive than HPV testing for a glandular lesion.
Photo: Courtesy of Dennis O’Conner, MD.

Similar results were described by Katki and coworkers in a large HMO screening population in the United States, in which Pap–/HPV+ women had half the risk of cancer over the subsequent 5 years, compared with women who were negative by Pap testing only (3.2 cases for every 100,000 women, compared with 7.5 cases, respectively). Of the total cases of CIN 3+ found, 35% of cases of CIN 3 and adenocarcinoma in situ (AIS) (FIGURE 1) were detected in women Pap-/HPV+, as were 29% of cancers. Cytology has been shown, in almost all studies, to be less sensitive for glandular lesions; it isn’t surprising, therefore, that 63% of adenocarcinomas found in this study population were detected by HPV testing only.

These results appear to provide overwhelming evidence of the benefit of including HPV testing in screening programs for cervical cancer.³

Dilemma: How do we best manage women who are Pap–/HPV+?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Although co-testing appears to reduce the risk of cervical cancer—allowing a safer margin for Pap-negative plus HPV-negative (Pap–/HPV–) women if they miss by up to 2 years their 3-year recommended screening—the question remains: What is the best way to manage Pap–/HPV+ women?

The primary recommendation by both the American Society for Colposcopy and Cervical Pathology (ASCCP) and ACOG is to re-screen them in 12 months, rather than send them immediately for colposcopy. Why? Because HPV infection 1) is relatively common among women who do not have CIN 2, 3 or invasive cervical cancer and 2) most often resolves without causing significant disease.

But re-screening these patients in 12 months negates much of the benefit of the high clinical sensitivity of HPV testing because it could lead to significant delay in the diagnosis and treatment of some women who already have either cervical cancer or advanced CIN 3 that might progress to cancer before their next evaluation. This concern is supported by the findings of the studies I discussed earlier.^1-3

Although cervical cancer missed at cytology screening is uncommon, 44 cervical cancers were reported by Kinney and coworkers in a large screening population in women who had one or more Pap–/HPV+ co-test results (18 had two or more Pap–/HPV+ results before diagnosis). More than 60% had cervical adenocarcinoma, which is more than three times the normal proportion of glandular cancer to squamous cervical cancer—again highlighting the relative insensitivity of cytology to detect glandular lesions.

Other drawbacks of waiting 12 months for further evaluation include 1) prolonged uncertainty for the patient and 2) the potential for losing her to follow-up, which occurs in as many as 50% of subjects in many studies.

Therefore, finding patients who are at greatest risk of CIN 2+ among the larger group of Pap–/HPV+ women, and referring them immediately for colposcopy, should provide great benefit.

Note that the 2006 ASCCP guidelines included a statement that, once an FDA-approved test for HPV 16, 18 was available, triage of Pap–/HPV+ patients who are positive for HPV 16, 18 could identify a majority at greatest risk of CIN 2,3+ and who would therefore benefit most by referral for colposcopy. In contrast, patients at lower risk (i.e., positive for any of the other 12 HPV types but not for types 16 and 18) would be better managed by repeating co-testing in 12 months—referring for colposcopy only those who are found again to be HPV+ or who have an abnormal Pap test.

In the next section of this Update, I explore recent evidence about the important role played by HPV 16, 18 in cervical carcinogenesis.

HPV 16, 18 pose long-term risk for CIN 3+ and cervical Ca

Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–1488.

The most compelling prediction of the risk of CIN 3+ in cases of either single (incident) or persistent high-risk HPV detection comes from a 13-year follow-up study out of Denmark. More than 8,600 Danish women, 20 to 29 years old at enrollment, were tested twice, 2 years apart, for HPV by the Hybrid Capture 2 High-Risk (HC2 HR) HPV DNA Test (Qiagen) and by line-blot assays for type-specific HPV.

Subjects were followed subsequently with routine screening; data on their overall long-term risk of CIN 3+ was obtained from the national Danish Pathology Data Bank. Among those who tested positive for HPV 16, absolute risk of CIN 3+ within 12 years of incident detection was 26.7%; for HPV 18, it was 19.1%—both percentages markedly higher than the 6% risk for women who tested positive for a panel of 10 other high-risk HPV types (also not including HPV 31, 33).

FIGURE 2 Over time, risk of CIN 3+ rises in all subpopulations infected by high-risk HPV

Shown is the absolute risk for CIN 3+ during follow-up among women who have HPV 16 persistence (red line), Hybrid Capture 2 High-Risk HPV DNA Test (HC2 HR) persistence for a panel of 13 high-risk HPV types (blue), incident or newly detected HPV 16 infection (i.e., HPV 16-negative at first examination and HPV 16-positive at second examination) (pink), and women with an incident high-risk HPV infection (i.e., negative for high-risk HPV by HC2 HR at first examination and positive at second examination) (green). For comparison, the dashed purple line shows the nearly flat absolute risk of CIN 3+ for women who are negative for high-risk HPV by HC2 HR at both examinations.
Source: Kjaer et al, 2010. Reproduced by permission of the publisher, Oxford University Press.

Risk associated with HPV 16. The most successfully persistent viral type was 16; just under 30% of subjects who were HPV 16+ on the first test remained HPV 16+ on the second test 2 years later. For this 30% subset, the risk of CIN 3+ was 8.9% at 3 years; 23.8% at 5 years; and an astonishing 47.4% at 12 years (FIGURE 2). In other words, almost half of subjects who had persistent HPV 16 in their 20s developed CIN 3 or cancer within 12 years. In contrast, the absolute risk for developing CIN 3+ within 12 years of a single negative HPV test was only 3%.

HPV 18. Viral type 18 was nearly as likely to persist as HPV 16; when persistent, it resulted in CIN 3+ in just under 30% of subjects within 12 years and tended to result in CIN 3+ that was detected later.

Using HPV 16, 18 testing to improve the management of Pap–/HPV+ women

Two more HPV tests are now FDA-approved for clinical use

In the 2006 Update on Cervical Disease [available in the archive at www.obgmanagement.com], I noted the importance of HPV 16, 18 in cervical carcinogenesis and observed that a test for these two viral types was on the horizon. It wasn’t until 2009 approval of the Cervista HPV DNA HR Test (Hologic), however, that such a test became available.

In 2011, two more tests were approved:

• cobas 4800 HPV DNA
• Aptima mRNA HPV.

Like Cervista, the cobas 4800 (Roche) is FDA-approved to detect HPV DNA types 16 and 18 individually; Gen-Probe’s Aptima HPV test is the first HPV E6,E7 mRNA test approved in the US; the company plans to add an HPV 16, 18 mRNA test. The addition of one, perhaps two, new HPV 16, 18 genotyping tests expands the opportunity for you to improve the management of Pap–/HPV+ patients.

Let’s look at new data that support testing of Pap–/HPV+ women for HPV 16, 18.

Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL; ATHENA (Addressing THE Need for Advanced HPV Diagnostics) Study Group. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4):578–586.

Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol. 2011;12(9):880–890.

Data to support the application to the FDA for approval of the cobas 4800 was provided by the ATHENA Trial, the largest (47,208 women) cervical screening trial of US women to assess the performance of HPV DNA testing with individual genotyping for HPV 16, 18, compared with the Pap.

Wright and co-workers. These investigators evaluated the subset of 32,260 women 30 years and older who had negative cytology. The overall prevalence of Pap–/HPV+ was 6.7%. Just over one quarter of the Pap–/HPV+ women (1.5% of the subset population) were positive for HPV 16 or 18, or both.

As has been shown in other studies, the overall prevalence of HPV declined with age, as did the prevalence of HPV 16, 18. The estimated absolute risk of CIN 3+ at colposcopy for women who were Pap–/HPV+ was only 4.1%, but their relative risk—that is, compared with women in whom both tests were negative—was 14.4%. The absolute risk for CIN 3+ increased to 9.8% for Pap-negative women who tested positive for HPV 16 or 18, or both, and to 11.7% in women who tested positive for HPV 16 only.

Ongoing work by Castle and colleagues. In a seminal 2007 article on risk management, Castle and colleagues proposed that women who had an absolute risk of CIN 3+ of ≥10% across 2–3 years of follow-up should have colposcopy.⁴ These data, therefore, clearly support the recommendation of ASCCP that Pap–/HPV 16+ and (or) HPV 18+ women should be referred for colposcopy (FIGURE 3).

FIGURE 3 Managing risk of CIN 3+ across 2 years of follow-up

This stratagem is based on 2006 ASCCP Consensus Guidelines, 2010 ACOG guidelines, and Castle and colleagues’ proposal in their 2007 article, “Risk assessment to guide the prevention of cervical cancer.”⁴
Figure courtesy of Thomas C. Wright, MD.

Now, in another review of the ATHENA results, expanded to a subset of women 25 years and older, Castle and co-workers reported that triage of Pap–/HPV+ women by testing for HPV 16, 18 detected 72% of all CIN 3+ that was missed by cytology alone. Because only 18% of Pap–/HPV+ women were positive for HPV 16, 18, the majority (i.e., 82% who were ≥25 years and 78% who were ≥30 years) could be reassured that their risk was sufficiently low that it could be best managed by repeating co-testing in 1 year. This avoids delaying the diagnosis of nearly three quarters of the Pap–/HPV+ women who have CIN 3+, without overburdening colposcopy services.

The ATHENA trial is ongoing; eventually, results from 3 years of follow-up of these women will be evaluated. The findings should add important information about the total burden of cervical precancer detected over a longer period after a Pap–/HPV+ result, with or without testing positive for HPV 16, 18.

We want to hear from you! Tell us what you think.

Dr. Cox is a consultant to Gen-Probe, OncoHealth, and Roche, and serves on the Data and Safety Monitoring Committee (DSMB) for Merck HPV vaccine trials. He is a speaker for Bradley Pharmaceuticals.

The American Cancer Society estimates that approximately 12,700 new cases of invasive cervical cancer were diagnosed in 2011 in the United States; nearly 4,300 of those women will die of the disease, the Society projects.¹ Great disparities in prevalence and incidence persist, with the rate of cervical cancer 1) highest in Latino women and 2) about 50% higher in African-American women than in non-Latino white women.

Because approximately 60% of cervical cancers occur in women who don’t undergo any screening for the disease, or who undergo only very infrequent screening, bringing more women in to be screened is most important. For women who are screened very infrequently, providing testing with the longest interval that provides safety should also reduce their risk of cancer.

Two advances have the potential to provide huge benefit in reducing the risk of cervical cancer: 1) increasing utilization of human papillomavirus (HPV) testing with Pap testing (so-called co-testing) for screening women 30 years and older and 2) widespread administration of the HPV vaccine to girls before they begin sexual activity. Regrettably, the promise of the HPV vaccine has not yet been fulfilled: Vaccine uptake (all three doses) among the primary target population hasn’t even reached 40%. And co-testing continues to be underutilized—in part because the best management strategy for women who have a negative Pap test result but a positive HPV test result (written here as “Pap–/HPV+”) has been less than clear.

Disappointments aside, 2011 did bring us a wealth of data on 1) the likely value of co-testing in preventing cervical cancer, and 2) improved management strategies for Pap–/HPV+ women—the areas of practice that I’ve made the focus of this year’s Update. The first question to ask: Does co-testing reduce the risk of cervical cancer more than current screening strategies that employ the Pap test?

Primary cytology (Pap test) screening (above) augmented by HPV testing—so-called co-testing—appears to cut the long-term risk of cervical Ca. Consider making a co-testing stratagem part of your practice, urges author Dr. J. Thomas Cox.

Will co-testing reduce the rate of cervical Ca to a greater degree than Pap screening has?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012;13(1):78–88.

Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7):663–672.

Recent studies have brought us closer to answering this question—and data certainly appear to suggest that the answer is “Yes.” Evidence from randomized controlled trials, prospective long-term cohort trials, and a large US screening population show that introducing HPV testing into cervical cancer screening could reduce cervical cancer incidence in women age ≥30—and even cervical cancer mortality.

I discussed one of these trials—the Italian NTCC trial—in the 2011 OBG Management Update on Cervical Disease [read that article in the archive at www.obgmanagement.com]; earlier detection and treatment of cervical intraepithelial neoplasia grade-3 (CIN 3) lesions in the first screening round in the co-tested group were proposed as the reasons that no cancers were detected in the second screening round (nine cancers were detected in the women having cytology only).²

Similar results were reported in the POBASCAM study from the Netherlands, in which more than 44,000 women were randomized to co-testing or screening with cytology alone, then re-screened 5 years later. As in the NTCC trial, more cases of CIN 3+ were detected and treated at the initial screen by co-testing than by cytology alone (i.e., projected out to 79 additional cases of CIN 3 and 30 additional cancers for every 100,000 women screened), with fewer cases of CIN 3+ detected in the co-tested group in the subsequent 5 years than in the cytology-only group (again, projected out to 24 fewer cases of CIN 3 and 10 fewer cancers for every 100,000 women).

(In a review of these study findings, experts at the National Cancer Institute [NCI] estimated that co-testing in POBASCAM reduced the risk of cervical cancer to only 2.2 cancers for every 100,000 women a year—demonstrating the safety of a 5-year screening interval.³) This means that women testing Pap–/HPV–, who are best screened at 3-year intervals, would be safe with an interval as long as 5 years—providing greater protection for irregularly screened women.

FIGURE 1 Cervical adenocarcinoma in situ

Cervical AIS demonstrated in a cytology specimen. Most studies have shown that cytology is less sensitive than HPV testing for a glandular lesion.
Photo: Courtesy of Dennis O’Conner, MD.

Similar results were described by Katki and coworkers in a large HMO screening population in the United States, in which Pap–/HPV+ women had half the risk of cancer over the subsequent 5 years, compared with women who were negative by Pap testing only (3.2 cases for every 100,000 women, compared with 7.5 cases, respectively). Of the total cases of CIN 3+ found, 35% of cases of CIN 3 and adenocarcinoma in situ (AIS) (FIGURE 1) were detected in women Pap-/HPV+, as were 29% of cancers. Cytology has been shown, in almost all studies, to be less sensitive for glandular lesions; it isn’t surprising, therefore, that 63% of adenocarcinomas found in this study population were detected by HPV testing only.

These results appear to provide overwhelming evidence of the benefit of including HPV testing in screening programs for cervical cancer.³

Dilemma: How do we best manage women who are Pap–/HPV+?

Kinney W, Fetterman B, Cox JT, Lorey T, Flanagan T, Castle PE. Characteristics of 44 cervical cancers diagnosed following Pap-negative, high risk HPV-positive screening in routine clinical practice. Gynecol Oncol. 2011;121(2):309–313.

Although co-testing appears to reduce the risk of cervical cancer—allowing a safer margin for Pap-negative plus HPV-negative (Pap–/HPV–) women if they miss by up to 2 years their 3-year recommended screening—the question remains: What is the best way to manage Pap–/HPV+ women?

The primary recommendation by both the American Society for Colposcopy and Cervical Pathology (ASCCP) and ACOG is to re-screen them in 12 months, rather than send them immediately for colposcopy. Why? Because HPV infection 1) is relatively common among women who do not have CIN 2, 3 or invasive cervical cancer and 2) most often resolves without causing significant disease.

But re-screening these patients in 12 months negates much of the benefit of the high clinical sensitivity of HPV testing because it could lead to significant delay in the diagnosis and treatment of some women who already have either cervical cancer or advanced CIN 3 that might progress to cancer before their next evaluation. This concern is supported by the findings of the studies I discussed earlier.^1-3

Although cervical cancer missed at cytology screening is uncommon, 44 cervical cancers were reported by Kinney and coworkers in a large screening population in women who had one or more Pap–/HPV+ co-test results (18 had two or more Pap–/HPV+ results before diagnosis). More than 60% had cervical adenocarcinoma, which is more than three times the normal proportion of glandular cancer to squamous cervical cancer—again highlighting the relative insensitivity of cytology to detect glandular lesions.

Other drawbacks of waiting 12 months for further evaluation include 1) prolonged uncertainty for the patient and 2) the potential for losing her to follow-up, which occurs in as many as 50% of subjects in many studies.

Therefore, finding patients who are at greatest risk of CIN 2+ among the larger group of Pap–/HPV+ women, and referring them immediately for colposcopy, should provide great benefit.

Note that the 2006 ASCCP guidelines included a statement that, once an FDA-approved test for HPV 16, 18 was available, triage of Pap–/HPV+ patients who are positive for HPV 16, 18 could identify a majority at greatest risk of CIN 2,3+ and who would therefore benefit most by referral for colposcopy. In contrast, patients at lower risk (i.e., positive for any of the other 12 HPV types but not for types 16 and 18) would be better managed by repeating co-testing in 12 months—referring for colposcopy only those who are found again to be HPV+ or who have an abnormal Pap test.

In the next section of this Update, I explore recent evidence about the important role played by HPV 16, 18 in cervical carcinogenesis.

HPV 16, 18 pose long-term risk for CIN 3+ and cervical Ca

Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102(19):1478–1488.

The most compelling prediction of the risk of CIN 3+ in cases of either single (incident) or persistent high-risk HPV detection comes from a 13-year follow-up study out of Denmark. More than 8,600 Danish women, 20 to 29 years old at enrollment, were tested twice, 2 years apart, for HPV by the Hybrid Capture 2 High-Risk (HC2 HR) HPV DNA Test (Qiagen) and by line-blot assays for type-specific HPV.

Subjects were followed subsequently with routine screening; data on their overall long-term risk of CIN 3+ was obtained from the national Danish Pathology Data Bank. Among those who tested positive for HPV 16, absolute risk of CIN 3+ within 12 years of incident detection was 26.7%; for HPV 18, it was 19.1%—both percentages markedly higher than the 6% risk for women who tested positive for a panel of 10 other high-risk HPV types (also not including HPV 31, 33).

FIGURE 2 Over time, risk of CIN 3+ rises in all subpopulations infected by high-risk HPV

Shown is the absolute risk for CIN 3+ during follow-up among women who have HPV 16 persistence (red line), Hybrid Capture 2 High-Risk HPV DNA Test (HC2 HR) persistence for a panel of 13 high-risk HPV types (blue), incident or newly detected HPV 16 infection (i.e., HPV 16-negative at first examination and HPV 16-positive at second examination) (pink), and women with an incident high-risk HPV infection (i.e., negative for high-risk HPV by HC2 HR at first examination and positive at second examination) (green). For comparison, the dashed purple line shows the nearly flat absolute risk of CIN 3+ for women who are negative for high-risk HPV by HC2 HR at both examinations.
Source: Kjaer et al, 2010. Reproduced by permission of the publisher, Oxford University Press.

Risk associated with HPV 16. The most successfully persistent viral type was 16; just under 30% of subjects who were HPV 16+ on the first test remained HPV 16+ on the second test 2 years later. For this 30% subset, the risk of CIN 3+ was 8.9% at 3 years; 23.8% at 5 years; and an astonishing 47.4% at 12 years (FIGURE 2). In other words, almost half of subjects who had persistent HPV 16 in their 20s developed CIN 3 or cancer within 12 years. In contrast, the absolute risk for developing CIN 3+ within 12 years of a single negative HPV test was only 3%.

HPV 18. Viral type 18 was nearly as likely to persist as HPV 16; when persistent, it resulted in CIN 3+ in just under 30% of subjects within 12 years and tended to result in CIN 3+ that was detected later.

Using HPV 16, 18 testing to improve the management of Pap–/HPV+ women

Two more HPV tests are now FDA-approved for clinical use

In the 2006 Update on Cervical Disease [available in the archive at www.obgmanagement.com], I noted the importance of HPV 16, 18 in cervical carcinogenesis and observed that a test for these two viral types was on the horizon. It wasn’t until 2009 approval of the Cervista HPV DNA HR Test (Hologic), however, that such a test became available.

In 2011, two more tests were approved:

• cobas 4800 HPV DNA
• Aptima mRNA HPV.

Like Cervista, the cobas 4800 (Roche) is FDA-approved to detect HPV DNA types 16 and 18 individually; Gen-Probe’s Aptima HPV test is the first HPV E6,E7 mRNA test approved in the US; the company plans to add an HPV 16, 18 mRNA test. The addition of one, perhaps two, new HPV 16, 18 genotyping tests expands the opportunity for you to improve the management of Pap–/HPV+ patients.

Let’s look at new data that support testing of Pap–/HPV+ women for HPV 16, 18.

Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL; ATHENA (Addressing THE Need for Advanced HPV Diagnostics) Study Group. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4):578–586.

Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol. 2011;12(9):880–890.

Data to support the application to the FDA for approval of the cobas 4800 was provided by the ATHENA Trial, the largest (47,208 women) cervical screening trial of US women to assess the performance of HPV DNA testing with individual genotyping for HPV 16, 18, compared with the Pap.

Wright and co-workers. These investigators evaluated the subset of 32,260 women 30 years and older who had negative cytology. The overall prevalence of Pap–/HPV+ was 6.7%. Just over one quarter of the Pap–/HPV+ women (1.5% of the subset population) were positive for HPV 16 or 18, or both.

As has been shown in other studies, the overall prevalence of HPV declined with age, as did the prevalence of HPV 16, 18. The estimated absolute risk of CIN 3+ at colposcopy for women who were Pap–/HPV+ was only 4.1%, but their relative risk—that is, compared with women in whom both tests were negative—was 14.4%. The absolute risk for CIN 3+ increased to 9.8% for Pap-negative women who tested positive for HPV 16 or 18, or both, and to 11.7% in women who tested positive for HPV 16 only.

Ongoing work by Castle and colleagues. In a seminal 2007 article on risk management, Castle and colleagues proposed that women who had an absolute risk of CIN 3+ of ≥10% across 2–3 years of follow-up should have colposcopy.⁴ These data, therefore, clearly support the recommendation of ASCCP that Pap–/HPV 16+ and (or) HPV 18+ women should be referred for colposcopy (FIGURE 3).

FIGURE 3 Managing risk of CIN 3+ across 2 years of follow-up

This stratagem is based on 2006 ASCCP Consensus Guidelines, 2010 ACOG guidelines, and Castle and colleagues’ proposal in their 2007 article, “Risk assessment to guide the prevention of cervical cancer.”⁴
Figure courtesy of Thomas C. Wright, MD.

Now, in another review of the ATHENA results, expanded to a subset of women 25 years and older, Castle and co-workers reported that triage of Pap–/HPV+ women by testing for HPV 16, 18 detected 72% of all CIN 3+ that was missed by cytology alone. Because only 18% of Pap–/HPV+ women were positive for HPV 16, 18, the majority (i.e., 82% who were ≥25 years and 78% who were ≥30 years) could be reassured that their risk was sufficiently low that it could be best managed by repeating co-testing in 1 year. This avoids delaying the diagnosis of nearly three quarters of the Pap–/HPV+ women who have CIN 3+, without overburdening colposcopy services.

The ATHENA trial is ongoing; eventually, results from 3 years of follow-up of these women will be evaluated. The findings should add important information about the total burden of cervical precancer detected over a longer period after a Pap–/HPV+ result, with or without testing positive for HPV 16, 18.

We want to hear from you! Tell us what you think.

In the March 2006 “Update on Cervical Disease,” I began with Prof. Margaret Stanley’s exclamation “It could be the end of the affair with HPV!” That Update covered three major areas that have been nudging us closer to the possibility of someday ending cervical cancer.

I thought it time to revisit those three practical advances to see how we’re doing. As you’ll read, much has happened; one exciting prospect in 2006—human papillomavirus (HPV) vaccination—has become established in everyday practice. On the other hand, primary screening with an HPV plus a Pap test (so-called co-testing) has not yet fulfilled its promise, and type-specific HPV testing for HPV 16 and 18, expected in 2006 to be “just around the corner,” is still … just around that corner.

And it isn’t just medicine that has changed. The World of 2009 is a markedly different place than the World of 2006. The economy of the United States is rockier than at any time since the Great Depression, and the skyrocketing cost of medical care has made health-care cost containment more important a goal than it ever has been.

So, allow me to reexamine what was “new in 2006” for cervical cancer prevention and compare where we are in 2009—thanks to interesting, important research and the effects on health care of an economic squeeze that we could not have foretold 3 years ago. I’ll also make an educated prediction about where cervical cancer prevention may be headed in, say, the next 3 years or so.

1 “More sensitive and more objective screening” inches closer

Naucler P, Ryd W, Törnberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009;101:88–99.

Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin. 2007;57:105–111.

Dillner J, Rebolj M, Birembaut P, et al; Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.

Comforting combo: Negative Pap and HPV tests

In 2006, I discussed the Level-A evidence, cited in the 2005 ACOG Practice Bulletin, that women who have a negative HPV test and a negative Pap (i.e., a co-testing protocol) have a risk of approximately 1 in 1,000 of an unidentified CIN 2,3 or cervical cancer and, therefore, do not need another Pap or HPV test for at least another 3 years. This would seem compelling evidence of the efficacy and safety of co-testing, so the expectation might be that this cervical screening strategy would quickly become the primary protocol for women 30 years or older.

But not so fast! Even though a recent Centers for Disease Control and Prevention (CDC) survey indicates that 66% of clinicians who provide cervical screening already used co-testing by 2004,¹ recent estimates are that only one third or fewer of women 30 years or older are being screened with a Pap test + HPV test. What does this mean? Possibly, that co-testing is used by a majority of clinicians, but not routinely. There are, likely, a number of reasons that co-testing has not become standard, but hesitancy to move beyond the annual Pap test is at the top of the list.

Will we move beyond tradition?

Providing an annual Pap test to our patients has reduced the incidence of cervical cancer from second among cancers in women to 11th, and mortality from second to 113th. But a program of annual cervical cytology is not cost-efficient² even if it is protective for most women, and the degree of protection declines among women who are screened irregularly.

Screening can be made more cost-effective by extending the screening interval. One option is to repeat the Pap every 2 or 3 years, instead of annually, for women who have had three consecutive normal Pap tests. The additional risk of cervical cancer that results from extending the screening interval to 3 years is estimated to be 3 to 5 cases for every 100,000 women³ —numbers that are small but that are unacceptable to many, considering the great potential for preventing cervical cancer.

The other option is to add HPV testing to screening. Because an HPV test is more sensitive for CIN 2,3, a negative result provides long-lasting reassurance against cancer risk.

Enter, economics. Adding an HPV test to the screen without increasing the interval is not cost-effective: It increases overdiagnosis and overmanagement and, thereby, harm.

Moving to less frequent screening is the only option for improving the cost effectiveness of cervical cancer prevention; less frequent screening reduces not only 1) the number of tests but also 2) detection of transient HPV infections not destined to progress and 3) overmanagement and treatment of such benign infections. And the high sensitivity and long-term predictive value of an HPV test ensures that moving to a longer interval isn’t likely to put women at more risk even if the next screen exceeds 3 years. Major studies confirm this margin of safety and validate a move to less frequent screening. Here’s what we learned in the past year.

In search of an optimal protocol

Most research on co-testing continues to come from Europe, where organized screening programs have facilitated large studies.

Compared with screening by cytology alone, co-testing that included 1) referral to colposcopy of all women who had an abnormal Pap and 2) testing for type-specific HPV persistence at 12 months for women who initially had a normal Pap and a positive HPV test resulted in a 35% increase in sensitivity for detecting CIN 3+, with only a modest reduction in positive predictive value. The researchers noted, however, that the gain in sensitivity came at the expense of doubling screening tests because screening in Sweden already occurs at a 3-year interval.

Naucler and colleagues used the database from the intervention arm (n=6,257 women) of a population-based randomized trial (the Swedescreen Trial), in which a conventional Pap smear and HPV test were obtained from women 32 to 38 years old, to evaluate the efficacy of 10 cervical screening strategies based on HPV DNA testing alone, cytology alone, and co-testing with both tests.

Solomon and co-workers estimated that, in the very near future, 75 million Paps will be performed each year if we don’t change our screening strategy from annual cervical cytology. If all screened women younger than 30 years had a liquid-based Pap every 2 years as recommended by the ACS, however, and if all screened women 30 years or older had a Pap test and an HPV test every 3 years, the number of annual Paps would decline to 34 million. Because this protocol requires a similar number of HPV tests for women older than 30 years, the total number of primary screening tests (HPV + Pap tests) would be only marginally less than the Paps performed at the present interval. But it is expected that less frequent screening would also reduce the number of transient HPV-induced cytologic events detected that require follow-up.

Are there other options?

Additional savings are possible if 1) both the Pap test and the HPV test did not need to be performed together or 2) the screening interval could be longer than Solomon described.

Naucler and colleagues clearly demonstrated that the most effective of the 10 screening options they evaluated was screening with an HPV test first (the most sensitive test) followed by a Pap test (the most specific test) only on women who have a positive HPV test. This protocol increased the sensitivity for CIN 3+ by 30% over the detection rate when the Pap was the only screening test, maintained a high positive predictive value, and increased the number of screening tests over the triennial “Pap-only” protocol by just 12%. In the United States, this approach would significantly decrease the number of screening tests, and should decrease costs, compared with the number of tests and costs associated with the traditional annual Pap test.

However, whether co-testing will ever be replaced by an HPV test as the sole primary screen depends on whether we are willing to accept a small decrement in protection in exchange for a major gain in cost effectiveness. In the past, safety has trumped but, in every aspect of health care to come, this will be the trade-off debated if, as a nation, we are to make our health care more affordable.

Can a longer HPV screening interval adequately protect patients?

A basic concern that clinicians have with the 3-year screening interval is that some women may not come in for screening until 4 or 5, or even more, years. Their concern is justified; numerous studies have confirmed that extending the screening interval beyond 3 years for women screened by cytology significantly decreases protection.

How protected would women be if they were screened with an HPV test? Dillner and colleagues demonstrated in their study that women who have a negative HPV test could have their interval safely extended for at least 6 years. Their work suggests that women who are screened infrequently would be significantly protected well beyond the 3-year interval now recommended in the United States with co-testing. However, it is important to point out that no screening test is perfect, and the reduction of cancer risk to zero is unlikely.

2 “Better management of screen positives”—we wait for new testing technology

Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader human papillomavirus (HPV) assay and the Digene HPV hybrid capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol. 2008;46:1641–1646.

Wong AK, Chan RC, Nichols WS, Bose S. Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical Papanicolaou smears with atypical squamous cells of undetermined significance. Cancer. 2009;115:823–832.

Castle PE, Dockter J, Giachetti C, et al. A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin Cancer Res. 2007;13:2599–2605.

Type-specific HPV testing identifies highest risk

By 2006, it had become clear that testing for HPV types 16 and 18 would identify those HPV-positive women who are at highest risk of CIN 2,3+. Investigators introduced a potential management algorithm that would likely alter the care of Pap-/HPV+ women once such testing became available.

Three years later, however, type-specific HPV testing still isn’t available. Why not?

One reason may be that type-specific HPV testing is much more complicated than the molecular tests that we use to identify a single virus or bacterium (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae) because the test has to identify several or more HPV types in a single assay. Proof of clinical utility requires more complex clinical studies than required for other sexually transmitted infections that have a quick therapeutic solution.

As we end the first quarter of 2009, no new HPV test or marker has yet been approved by the Food and Drug Administration (FDA) for clinical use. However, one of the three most promising candidates, HPV DNA testing for HPV 16, 18 (Invader HPV DNA [Hologic]) may be close to approval, and another, based on detection of messenger RNA (mRNA) has begun clinical trials (Aptiva mRNA [GenProbe]).

The Invader HPV (Inv2) test detects 14 high-risk HPV subtypes that are grouped in three probe sets on the basis of their interrelatedness. Results are reported as positive or negative for the entire probe set, not for individual viral types. The probe sets are:

• A5/A6 (HPV types 51, 56, and 66)
• A7 (types 18, 39, 45, 59, and 68)
• A9 (types 16, 31, 33, 35, 52, and 58).

The types in the A7 probe set are found more often in glandular lesions, such as adenocarcinoma in situ. Types in the A9 group are more often responsible for the squamous lesions of CIN 3 and squamous cell cervical cancer (although types in both groups can cause either type of lesion).

HPV E6/E7 mRNA testing for high-risk types may correlate better with the severity of lesions than HPV DNA testing—because up-regulation of mRNA from the oncogene region of the HPV genome (E6 and E7) is likely to be more predictive of which HPV-infected women are most likely to persist and progress to a high-grade lesion and cancer.

Castle and co-workers reported in their study that subjects in their study tested positive for HPV E6/E7 mRNA in 94% of cases of CIN 3 (46 of 49 women) and in all five cases of cancer. Overall, fewer specimens that were not characterized by a high-grade lesion tested positive for HPV E6/E7 mRNA than for HPV DNA.

3 “HPV vaccine … in our offices”—is confirmed safe and efficacious

Joura EA, Kjaer SK, Wheeler CM, et al. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine. 2008;26:6844–6851.

Centers for Disease Control and Prevention (CDC). Syncope after vaccination—United States, January 2005–July 2007. MMWR Morb Mortal Wkly Rep. 2008;57:457–460.

Centers for Disease Control and Prevention (CDC). Information from FDA and CDC on Gardasil and its safety. Available at: http://www.cdc.gov/vaccinesafety/vaers/FDA_and_CDC_ Statement.htm. Accessed February 12, 2009.

Kuehn BM. CDC panel recommends vaccine for smokers; reviews HPV safety data. JAMA. 2008;300:2713–2714.

The vaccine that protects against certain types of HPV, and probably against cervical cancer caused by those types, wasn’t approved by the FDA when the March 2006 “Update on Cervical Disease” was published. Preapproval expectations were high at the time; what we have witnessed since approval of Gardasil (Merck) has, in fact, exceeded earlier expectations.

As of August 31, 2008, more than 20 million doses of Gardasil have been administered. A CDC survey of 3,000 US adolescents 13 to 17 years old showed that one of every four received at least one shot of the vaccine in 2007, the first full year after approval. This uptake of the HPV vaccine during its first year is significantly better than 12% for the meningococcal vaccine and 11% for Tdap in the year after their introduction.

Is the vaccine efficacious?

Recent data from Joura and colleagues, based on more than 6 years of follow-up of women immunized with the quadrivalent vaccine, have not shown any decrease in protection from CIN 3+. There has been concern, however, that falling antibody levels that have been noted, particularly against HPV type 18, may indicate reduced protection from high-grade squamous or glandular disease.

To clarify the matter, these investigators evaluated efficacy data on the 40% of vaccine subjects who were anti-HPV 18-seronegative at the end of the study. Despite the inability to document antibodies to HPV 18 in these subjects, efficacy against HPV 18-related CIN 3 or adenocarcinoma in situ remained high at 98.4% compared with the placebo group. Th ese results suggest that vaccine-induced protection is high despite lower-than-detectable anti-HPV 18 titers.

How safe is it?

The safety of the HPV vaccine was studied in seven clinical trials in more than 21,000 girls and women 9 to 26 years old before it was licensed. The conclusion was that this is a very safe vaccine. But much has been made in the media—and even in a few peer-reviewed articles in the medical literature—that nevertheless questions the safety of Gardasil, and there is little doubt that clinicians who administer the vaccine have been bombarded with questions about this by their patients.

As of August 31, 2008, there were 10,326 Vaccine Adverse Event Reporting System (VAERS) reports of adverse events following Gardasil vaccination in the United States: 94% were considered nonserious and 6% were serious. These numbers appear great, but a 6% rate of serious adverse events is only about one half of the 10% to 15% rate observed after other vaccines made their debut.

VAERS, one of three systems utilized to monitor the safety of all vaccines after licensing and marketing in the United States, is open to the public. This means that it collects data without verifying the relationship of the adverse event to the vaccine other than proximity of timing. In a joint July 2008 Web-site posting, the CDC and FDA said: “In some media reports and on some web sites on the Internet, VAERS reports are presented as verified cases of vaccine deaths and injuries. Statements such as these misrepresent the nature of VAERS surveillance system.”

As part of ongoing surveillance, the CDC met in October 2008 to review Gardasil safety data. A synopsis of findings follows.

Minor adverse events

Reports of nonserious adverse events include syncope, pain and swelling at the site of injection (the arm), headache, nausea, and fever. The most common side effect reported to VAERS is syncope.

The FDA-CDC report emphasizes that syncope as a vasovagal reaction can occur after any vaccination, particularly in an adolescent. Syncope is not serious unless the patient is injured as she falls.

Major adverse events

Of course, greatest concern over the safety of the HPV vaccine is with reports of major adverse events following administration—including death. The October 2008 FDACDC review says that careful evaluation by medical experts of all serious reports has not found a common medical pattern to suggest that any were caused by the vaccine. Here is a summary of serious adverse-event reports submitted to VAERS between June 8, 2006, and August 31, 2008.

Guillain-Barré syndrome has been reported after vaccination with Gardasil. This rare disorder occurs in 1 or 2 of every 100,000 adolescents, and can be caused by any of several infectious agents. The FDA and CDC report no indication that Gardasil increases the rate of Guillain-Barré syndrome in females above the rate expected in the general population.

Blood clots have been reported in the heart, lungs, and legs of women after vaccination with Gardasil. In most cases, thorough evaluation identified other risk factors for clotting, including use of an oral contraceptive.

Death. There have been 27 reports in the United States of death among females who have been given the vaccine. The FDA-CDC review of each case has not documented a common pattern to these deaths to suggest that the vaccine was the cause of death. Here is a breakdown of those 27 reports:

• 3 related to diabetes or heart failure
• 3 to a viral illness, including meningitis
• 2 to drug use
• 2 to blood clots
• 5 are still being evaluated
• 1 report of a seizure disorder (patient had a history of seizures)
• 11 reports in which the cause of death is: unknown; cannot be evaluated because the person’s name or the death is unverified; or is still under review while medical records are obtained.

In the March 2006 “Update on Cervical Disease,” I began with Prof. Margaret Stanley’s exclamation “It could be the end of the affair with HPV!” That Update covered three major areas that have been nudging us closer to the possibility of someday ending cervical cancer.

I thought it time to revisit those three practical advances to see how we’re doing. As you’ll read, much has happened; one exciting prospect in 2006—human papillomavirus (HPV) vaccination—has become established in everyday practice. On the other hand, primary screening with an HPV plus a Pap test (so-called co-testing) has not yet fulfilled its promise, and type-specific HPV testing for HPV 16 and 18, expected in 2006 to be “just around the corner,” is still … just around that corner.

And it isn’t just medicine that has changed. The World of 2009 is a markedly different place than the World of 2006. The economy of the United States is rockier than at any time since the Great Depression, and the skyrocketing cost of medical care has made health-care cost containment more important a goal than it ever has been.

So, allow me to reexamine what was “new in 2006” for cervical cancer prevention and compare where we are in 2009—thanks to interesting, important research and the effects on health care of an economic squeeze that we could not have foretold 3 years ago. I’ll also make an educated prediction about where cervical cancer prevention may be headed in, say, the next 3 years or so.

1 “More sensitive and more objective screening” inches closer

Naucler P, Ryd W, Törnberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009;101:88–99.

Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin. 2007;57:105–111.

Dillner J, Rebolj M, Birembaut P, et al; Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.

Comforting combo: Negative Pap and HPV tests

In 2006, I discussed the Level-A evidence, cited in the 2005 ACOG Practice Bulletin, that women who have a negative HPV test and a negative Pap (i.e., a co-testing protocol) have a risk of approximately 1 in 1,000 of an unidentified CIN 2,3 or cervical cancer and, therefore, do not need another Pap or HPV test for at least another 3 years. This would seem compelling evidence of the efficacy and safety of co-testing, so the expectation might be that this cervical screening strategy would quickly become the primary protocol for women 30 years or older.

But not so fast! Even though a recent Centers for Disease Control and Prevention (CDC) survey indicates that 66% of clinicians who provide cervical screening already used co-testing by 2004,¹ recent estimates are that only one third or fewer of women 30 years or older are being screened with a Pap test + HPV test. What does this mean? Possibly, that co-testing is used by a majority of clinicians, but not routinely. There are, likely, a number of reasons that co-testing has not become standard, but hesitancy to move beyond the annual Pap test is at the top of the list.

Will we move beyond tradition?

Providing an annual Pap test to our patients has reduced the incidence of cervical cancer from second among cancers in women to 11th, and mortality from second to 113th. But a program of annual cervical cytology is not cost-efficient² even if it is protective for most women, and the degree of protection declines among women who are screened irregularly.

Screening can be made more cost-effective by extending the screening interval. One option is to repeat the Pap every 2 or 3 years, instead of annually, for women who have had three consecutive normal Pap tests. The additional risk of cervical cancer that results from extending the screening interval to 3 years is estimated to be 3 to 5 cases for every 100,000 women³ —numbers that are small but that are unacceptable to many, considering the great potential for preventing cervical cancer.

The other option is to add HPV testing to screening. Because an HPV test is more sensitive for CIN 2,3, a negative result provides long-lasting reassurance against cancer risk.

Enter, economics. Adding an HPV test to the screen without increasing the interval is not cost-effective: It increases overdiagnosis and overmanagement and, thereby, harm.

Moving to less frequent screening is the only option for improving the cost effectiveness of cervical cancer prevention; less frequent screening reduces not only 1) the number of tests but also 2) detection of transient HPV infections not destined to progress and 3) overmanagement and treatment of such benign infections. And the high sensitivity and long-term predictive value of an HPV test ensures that moving to a longer interval isn’t likely to put women at more risk even if the next screen exceeds 3 years. Major studies confirm this margin of safety and validate a move to less frequent screening. Here’s what we learned in the past year.

In search of an optimal protocol

Most research on co-testing continues to come from Europe, where organized screening programs have facilitated large studies.

Compared with screening by cytology alone, co-testing that included 1) referral to colposcopy of all women who had an abnormal Pap and 2) testing for type-specific HPV persistence at 12 months for women who initially had a normal Pap and a positive HPV test resulted in a 35% increase in sensitivity for detecting CIN 3+, with only a modest reduction in positive predictive value. The researchers noted, however, that the gain in sensitivity came at the expense of doubling screening tests because screening in Sweden already occurs at a 3-year interval.

Naucler and colleagues used the database from the intervention arm (n=6,257 women) of a population-based randomized trial (the Swedescreen Trial), in which a conventional Pap smear and HPV test were obtained from women 32 to 38 years old, to evaluate the efficacy of 10 cervical screening strategies based on HPV DNA testing alone, cytology alone, and co-testing with both tests.

Solomon and co-workers estimated that, in the very near future, 75 million Paps will be performed each year if we don’t change our screening strategy from annual cervical cytology. If all screened women younger than 30 years had a liquid-based Pap every 2 years as recommended by the ACS, however, and if all screened women 30 years or older had a Pap test and an HPV test every 3 years, the number of annual Paps would decline to 34 million. Because this protocol requires a similar number of HPV tests for women older than 30 years, the total number of primary screening tests (HPV + Pap tests) would be only marginally less than the Paps performed at the present interval. But it is expected that less frequent screening would also reduce the number of transient HPV-induced cytologic events detected that require follow-up.

Are there other options?

Additional savings are possible if 1) both the Pap test and the HPV test did not need to be performed together or 2) the screening interval could be longer than Solomon described.

Naucler and colleagues clearly demonstrated that the most effective of the 10 screening options they evaluated was screening with an HPV test first (the most sensitive test) followed by a Pap test (the most specific test) only on women who have a positive HPV test. This protocol increased the sensitivity for CIN 3+ by 30% over the detection rate when the Pap was the only screening test, maintained a high positive predictive value, and increased the number of screening tests over the triennial “Pap-only” protocol by just 12%. In the United States, this approach would significantly decrease the number of screening tests, and should decrease costs, compared with the number of tests and costs associated with the traditional annual Pap test.

However, whether co-testing will ever be replaced by an HPV test as the sole primary screen depends on whether we are willing to accept a small decrement in protection in exchange for a major gain in cost effectiveness. In the past, safety has trumped but, in every aspect of health care to come, this will be the trade-off debated if, as a nation, we are to make our health care more affordable.

Can a longer HPV screening interval adequately protect patients?

A basic concern that clinicians have with the 3-year screening interval is that some women may not come in for screening until 4 or 5, or even more, years. Their concern is justified; numerous studies have confirmed that extending the screening interval beyond 3 years for women screened by cytology significantly decreases protection.

How protected would women be if they were screened with an HPV test? Dillner and colleagues demonstrated in their study that women who have a negative HPV test could have their interval safely extended for at least 6 years. Their work suggests that women who are screened infrequently would be significantly protected well beyond the 3-year interval now recommended in the United States with co-testing. However, it is important to point out that no screening test is perfect, and the reduction of cancer risk to zero is unlikely.

2 “Better management of screen positives”—we wait for new testing technology

Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader human papillomavirus (HPV) assay and the Digene HPV hybrid capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol. 2008;46:1641–1646.

Wong AK, Chan RC, Nichols WS, Bose S. Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical Papanicolaou smears with atypical squamous cells of undetermined significance. Cancer. 2009;115:823–832.

Castle PE, Dockter J, Giachetti C, et al. A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin Cancer Res. 2007;13:2599–2605.

Type-specific HPV testing identifies highest risk

By 2006, it had become clear that testing for HPV types 16 and 18 would identify those HPV-positive women who are at highest risk of CIN 2,3+. Investigators introduced a potential management algorithm that would likely alter the care of Pap-/HPV+ women once such testing became available.

Three years later, however, type-specific HPV testing still isn’t available. Why not?

One reason may be that type-specific HPV testing is much more complicated than the molecular tests that we use to identify a single virus or bacterium (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae) because the test has to identify several or more HPV types in a single assay. Proof of clinical utility requires more complex clinical studies than required for other sexually transmitted infections that have a quick therapeutic solution.

As we end the first quarter of 2009, no new HPV test or marker has yet been approved by the Food and Drug Administration (FDA) for clinical use. However, one of the three most promising candidates, HPV DNA testing for HPV 16, 18 (Invader HPV DNA [Hologic]) may be close to approval, and another, based on detection of messenger RNA (mRNA) has begun clinical trials (Aptiva mRNA [GenProbe]).

The Invader HPV (Inv2) test detects 14 high-risk HPV subtypes that are grouped in three probe sets on the basis of their interrelatedness. Results are reported as positive or negative for the entire probe set, not for individual viral types. The probe sets are:

• A5/A6 (HPV types 51, 56, and 66)
• A7 (types 18, 39, 45, 59, and 68)
• A9 (types 16, 31, 33, 35, 52, and 58).

The types in the A7 probe set are found more often in glandular lesions, such as adenocarcinoma in situ. Types in the A9 group are more often responsible for the squamous lesions of CIN 3 and squamous cell cervical cancer (although types in both groups can cause either type of lesion).

HPV E6/E7 mRNA testing for high-risk types may correlate better with the severity of lesions than HPV DNA testing—because up-regulation of mRNA from the oncogene region of the HPV genome (E6 and E7) is likely to be more predictive of which HPV-infected women are most likely to persist and progress to a high-grade lesion and cancer.

Castle and co-workers reported in their study that subjects in their study tested positive for HPV E6/E7 mRNA in 94% of cases of CIN 3 (46 of 49 women) and in all five cases of cancer. Overall, fewer specimens that were not characterized by a high-grade lesion tested positive for HPV E6/E7 mRNA than for HPV DNA.

3 “HPV vaccine … in our offices”—is confirmed safe and efficacious

Joura EA, Kjaer SK, Wheeler CM, et al. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine. 2008;26:6844–6851.

Centers for Disease Control and Prevention (CDC). Syncope after vaccination—United States, January 2005–July 2007. MMWR Morb Mortal Wkly Rep. 2008;57:457–460.

Centers for Disease Control and Prevention (CDC). Information from FDA and CDC on Gardasil and its safety. Available at: http://www.cdc.gov/vaccinesafety/vaers/FDA_and_CDC_ Statement.htm. Accessed February 12, 2009.

Kuehn BM. CDC panel recommends vaccine for smokers; reviews HPV safety data. JAMA. 2008;300:2713–2714.

The vaccine that protects against certain types of HPV, and probably against cervical cancer caused by those types, wasn’t approved by the FDA when the March 2006 “Update on Cervical Disease” was published. Preapproval expectations were high at the time; what we have witnessed since approval of Gardasil (Merck) has, in fact, exceeded earlier expectations.

As of August 31, 2008, more than 20 million doses of Gardasil have been administered. A CDC survey of 3,000 US adolescents 13 to 17 years old showed that one of every four received at least one shot of the vaccine in 2007, the first full year after approval. This uptake of the HPV vaccine during its first year is significantly better than 12% for the meningococcal vaccine and 11% for Tdap in the year after their introduction.

Is the vaccine efficacious?

Recent data from Joura and colleagues, based on more than 6 years of follow-up of women immunized with the quadrivalent vaccine, have not shown any decrease in protection from CIN 3+. There has been concern, however, that falling antibody levels that have been noted, particularly against HPV type 18, may indicate reduced protection from high-grade squamous or glandular disease.

To clarify the matter, these investigators evaluated efficacy data on the 40% of vaccine subjects who were anti-HPV 18-seronegative at the end of the study. Despite the inability to document antibodies to HPV 18 in these subjects, efficacy against HPV 18-related CIN 3 or adenocarcinoma in situ remained high at 98.4% compared with the placebo group. Th ese results suggest that vaccine-induced protection is high despite lower-than-detectable anti-HPV 18 titers.

How safe is it?

The safety of the HPV vaccine was studied in seven clinical trials in more than 21,000 girls and women 9 to 26 years old before it was licensed. The conclusion was that this is a very safe vaccine. But much has been made in the media—and even in a few peer-reviewed articles in the medical literature—that nevertheless questions the safety of Gardasil, and there is little doubt that clinicians who administer the vaccine have been bombarded with questions about this by their patients.

As of August 31, 2008, there were 10,326 Vaccine Adverse Event Reporting System (VAERS) reports of adverse events following Gardasil vaccination in the United States: 94% were considered nonserious and 6% were serious. These numbers appear great, but a 6% rate of serious adverse events is only about one half of the 10% to 15% rate observed after other vaccines made their debut.

VAERS, one of three systems utilized to monitor the safety of all vaccines after licensing and marketing in the United States, is open to the public. This means that it collects data without verifying the relationship of the adverse event to the vaccine other than proximity of timing. In a joint July 2008 Web-site posting, the CDC and FDA said: “In some media reports and on some web sites on the Internet, VAERS reports are presented as verified cases of vaccine deaths and injuries. Statements such as these misrepresent the nature of VAERS surveillance system.”

As part of ongoing surveillance, the CDC met in October 2008 to review Gardasil safety data. A synopsis of findings follows.

Minor adverse events

Reports of nonserious adverse events include syncope, pain and swelling at the site of injection (the arm), headache, nausea, and fever. The most common side effect reported to VAERS is syncope.

The FDA-CDC report emphasizes that syncope as a vasovagal reaction can occur after any vaccination, particularly in an adolescent. Syncope is not serious unless the patient is injured as she falls.

Major adverse events

Of course, greatest concern over the safety of the HPV vaccine is with reports of major adverse events following administration—including death. The October 2008 FDACDC review says that careful evaluation by medical experts of all serious reports has not found a common medical pattern to suggest that any were caused by the vaccine. Here is a summary of serious adverse-event reports submitted to VAERS between June 8, 2006, and August 31, 2008.

Guillain-Barré syndrome has been reported after vaccination with Gardasil. This rare disorder occurs in 1 or 2 of every 100,000 adolescents, and can be caused by any of several infectious agents. The FDA and CDC report no indication that Gardasil increases the rate of Guillain-Barré syndrome in females above the rate expected in the general population.

Blood clots have been reported in the heart, lungs, and legs of women after vaccination with Gardasil. In most cases, thorough evaluation identified other risk factors for clotting, including use of an oral contraceptive.

Death. There have been 27 reports in the United States of death among females who have been given the vaccine. The FDA-CDC review of each case has not documented a common pattern to these deaths to suggest that the vaccine was the cause of death. Here is a breakdown of those 27 reports:

• 3 related to diabetes or heart failure
• 3 to a viral illness, including meningitis
• 2 to drug use
• 2 to blood clots
• 5 are still being evaluated
• 1 report of a seizure disorder (patient had a history of seizures)
• 11 reports in which the cause of death is: unknown; cannot be evaluated because the person’s name or the death is unverified; or is still under review while medical records are obtained.

In the March 2006 “Update on Cervical Disease,” I began with Prof. Margaret Stanley’s exclamation “It could be the end of the affair with HPV!” That Update covered three major areas that have been nudging us closer to the possibility of someday ending cervical cancer.

I thought it time to revisit those three practical advances to see how we’re doing. As you’ll read, much has happened; one exciting prospect in 2006—human papillomavirus (HPV) vaccination—has become established in everyday practice. On the other hand, primary screening with an HPV plus a Pap test (so-called co-testing) has not yet fulfilled its promise, and type-specific HPV testing for HPV 16 and 18, expected in 2006 to be “just around the corner,” is still … just around that corner.

And it isn’t just medicine that has changed. The World of 2009 is a markedly different place than the World of 2006. The economy of the United States is rockier than at any time since the Great Depression, and the skyrocketing cost of medical care has made health-care cost containment more important a goal than it ever has been.

So, allow me to reexamine what was “new in 2006” for cervical cancer prevention and compare where we are in 2009—thanks to interesting, important research and the effects on health care of an economic squeeze that we could not have foretold 3 years ago. I’ll also make an educated prediction about where cervical cancer prevention may be headed in, say, the next 3 years or so.

1 “More sensitive and more objective screening” inches closer

Naucler P, Ryd W, Törnberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009;101:88–99.

Solomon D, Breen N, McNeel T. Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines. CA Cancer J Clin. 2007;57:105–111.

Dillner J, Rebolj M, Birembaut P, et al; Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;337:a1754.

Comforting combo: Negative Pap and HPV tests

In 2006, I discussed the Level-A evidence, cited in the 2005 ACOG Practice Bulletin, that women who have a negative HPV test and a negative Pap (i.e., a co-testing protocol) have a risk of approximately 1 in 1,000 of an unidentified CIN 2,3 or cervical cancer and, therefore, do not need another Pap or HPV test for at least another 3 years. This would seem compelling evidence of the efficacy and safety of co-testing, so the expectation might be that this cervical screening strategy would quickly become the primary protocol for women 30 years or older.

But not so fast! Even though a recent Centers for Disease Control and Prevention (CDC) survey indicates that 66% of clinicians who provide cervical screening already used co-testing by 2004,¹ recent estimates are that only one third or fewer of women 30 years or older are being screened with a Pap test + HPV test. What does this mean? Possibly, that co-testing is used by a majority of clinicians, but not routinely. There are, likely, a number of reasons that co-testing has not become standard, but hesitancy to move beyond the annual Pap test is at the top of the list.

Will we move beyond tradition?

Providing an annual Pap test to our patients has reduced the incidence of cervical cancer from second among cancers in women to 11th, and mortality from second to 113th. But a program of annual cervical cytology is not cost-efficient² even if it is protective for most women, and the degree of protection declines among women who are screened irregularly.

Screening can be made more cost-effective by extending the screening interval. One option is to repeat the Pap every 2 or 3 years, instead of annually, for women who have had three consecutive normal Pap tests. The additional risk of cervical cancer that results from extending the screening interval to 3 years is estimated to be 3 to 5 cases for every 100,000 women³ —numbers that are small but that are unacceptable to many, considering the great potential for preventing cervical cancer.

The other option is to add HPV testing to screening. Because an HPV test is more sensitive for CIN 2,3, a negative result provides long-lasting reassurance against cancer risk.

Enter, economics. Adding an HPV test to the screen without increasing the interval is not cost-effective: It increases overdiagnosis and overmanagement and, thereby, harm.

Moving to less frequent screening is the only option for improving the cost effectiveness of cervical cancer prevention; less frequent screening reduces not only 1) the number of tests but also 2) detection of transient HPV infections not destined to progress and 3) overmanagement and treatment of such benign infections. And the high sensitivity and long-term predictive value of an HPV test ensures that moving to a longer interval isn’t likely to put women at more risk even if the next screen exceeds 3 years. Major studies confirm this margin of safety and validate a move to less frequent screening. Here’s what we learned in the past year.

In search of an optimal protocol

Most research on co-testing continues to come from Europe, where organized screening programs have facilitated large studies.

Compared with screening by cytology alone, co-testing that included 1) referral to colposcopy of all women who had an abnormal Pap and 2) testing for type-specific HPV persistence at 12 months for women who initially had a normal Pap and a positive HPV test resulted in a 35% increase in sensitivity for detecting CIN 3+, with only a modest reduction in positive predictive value. The researchers noted, however, that the gain in sensitivity came at the expense of doubling screening tests because screening in Sweden already occurs at a 3-year interval.

Naucler and colleagues used the database from the intervention arm (n=6,257 women) of a population-based randomized trial (the Swedescreen Trial), in which a conventional Pap smear and HPV test were obtained from women 32 to 38 years old, to evaluate the efficacy of 10 cervical screening strategies based on HPV DNA testing alone, cytology alone, and co-testing with both tests.

Solomon and co-workers estimated that, in the very near future, 75 million Paps will be performed each year if we don’t change our screening strategy from annual cervical cytology. If all screened women younger than 30 years had a liquid-based Pap every 2 years as recommended by the ACS, however, and if all screened women 30 years or older had a Pap test and an HPV test every 3 years, the number of annual Paps would decline to 34 million. Because this protocol requires a similar number of HPV tests for women older than 30 years, the total number of primary screening tests (HPV + Pap tests) would be only marginally less than the Paps performed at the present interval. But it is expected that less frequent screening would also reduce the number of transient HPV-induced cytologic events detected that require follow-up.

Are there other options?

Additional savings are possible if 1) both the Pap test and the HPV test did not need to be performed together or 2) the screening interval could be longer than Solomon described.

Naucler and colleagues clearly demonstrated that the most effective of the 10 screening options they evaluated was screening with an HPV test first (the most sensitive test) followed by a Pap test (the most specific test) only on women who have a positive HPV test. This protocol increased the sensitivity for CIN 3+ by 30% over the detection rate when the Pap was the only screening test, maintained a high positive predictive value, and increased the number of screening tests over the triennial “Pap-only” protocol by just 12%. In the United States, this approach would significantly decrease the number of screening tests, and should decrease costs, compared with the number of tests and costs associated with the traditional annual Pap test.

However, whether co-testing will ever be replaced by an HPV test as the sole primary screen depends on whether we are willing to accept a small decrement in protection in exchange for a major gain in cost effectiveness. In the past, safety has trumped but, in every aspect of health care to come, this will be the trade-off debated if, as a nation, we are to make our health care more affordable.

Can a longer HPV screening interval adequately protect patients?

A basic concern that clinicians have with the 3-year screening interval is that some women may not come in for screening until 4 or 5, or even more, years. Their concern is justified; numerous studies have confirmed that extending the screening interval beyond 3 years for women screened by cytology significantly decreases protection.

How protected would women be if they were screened with an HPV test? Dillner and colleagues demonstrated in their study that women who have a negative HPV test could have their interval safely extended for at least 6 years. Their work suggests that women who are screened infrequently would be significantly protected well beyond the 3-year interval now recommended in the United States with co-testing. However, it is important to point out that no screening test is perfect, and the reduction of cancer risk to zero is unlikely.

2 “Better management of screen positives”—we wait for new testing technology

Ginocchio CC, Barth D, Zhang F. Comparison of the Third Wave Invader human papillomavirus (HPV) assay and the Digene HPV hybrid capture 2 assay for detection of high-risk HPV DNA. J Clin Microbiol. 2008;46:1641–1646.

Wong AK, Chan RC, Nichols WS, Bose S. Invader human papillomavirus (HPV) type 16 and 18 assays as adjuncts to HPV screening of cervical Papanicolaou smears with atypical squamous cells of undetermined significance. Cancer. 2009;115:823–832.

Castle PE, Dockter J, Giachetti C, et al. A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer. Clin Cancer Res. 2007;13:2599–2605.

Type-specific HPV testing identifies highest risk

By 2006, it had become clear that testing for HPV types 16 and 18 would identify those HPV-positive women who are at highest risk of CIN 2,3+. Investigators introduced a potential management algorithm that would likely alter the care of Pap-/HPV+ women once such testing became available.

Three years later, however, type-specific HPV testing still isn’t available. Why not?

One reason may be that type-specific HPV testing is much more complicated than the molecular tests that we use to identify a single virus or bacterium (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae) because the test has to identify several or more HPV types in a single assay. Proof of clinical utility requires more complex clinical studies than required for other sexually transmitted infections that have a quick therapeutic solution.

As we end the first quarter of 2009, no new HPV test or marker has yet been approved by the Food and Drug Administration (FDA) for clinical use. However, one of the three most promising candidates, HPV DNA testing for HPV 16, 18 (Invader HPV DNA [Hologic]) may be close to approval, and another, based on detection of messenger RNA (mRNA) has begun clinical trials (Aptiva mRNA [GenProbe]).

The Invader HPV (Inv2) test detects 14 high-risk HPV subtypes that are grouped in three probe sets on the basis of their interrelatedness. Results are reported as positive or negative for the entire probe set, not for individual viral types. The probe sets are:

• A5/A6 (HPV types 51, 56, and 66)
• A7 (types 18, 39, 45, 59, and 68)
• A9 (types 16, 31, 33, 35, 52, and 58).

The types in the A7 probe set are found more often in glandular lesions, such as adenocarcinoma in situ. Types in the A9 group are more often responsible for the squamous lesions of CIN 3 and squamous cell cervical cancer (although types in both groups can cause either type of lesion).

HPV E6/E7 mRNA testing for high-risk types may correlate better with the severity of lesions than HPV DNA testing—because up-regulation of mRNA from the oncogene region of the HPV genome (E6 and E7) is likely to be more predictive of which HPV-infected women are most likely to persist and progress to a high-grade lesion and cancer.

Castle and co-workers reported in their study that subjects in their study tested positive for HPV E6/E7 mRNA in 94% of cases of CIN 3 (46 of 49 women) and in all five cases of cancer. Overall, fewer specimens that were not characterized by a high-grade lesion tested positive for HPV E6/E7 mRNA than for HPV DNA.

3 “HPV vaccine … in our offices”—is confirmed safe and efficacious

Joura EA, Kjaer SK, Wheeler CM, et al. HPV antibody levels and clinical efficacy following administration of a prophylactic quadrivalent HPV vaccine. Vaccine. 2008;26:6844–6851.

Centers for Disease Control and Prevention (CDC). Syncope after vaccination—United States, January 2005–July 2007. MMWR Morb Mortal Wkly Rep. 2008;57:457–460.

Centers for Disease Control and Prevention (CDC). Information from FDA and CDC on Gardasil and its safety. Available at: http://www.cdc.gov/vaccinesafety/vaers/FDA_and_CDC_ Statement.htm. Accessed February 12, 2009.

Kuehn BM. CDC panel recommends vaccine for smokers; reviews HPV safety data. JAMA. 2008;300:2713–2714.

The vaccine that protects against certain types of HPV, and probably against cervical cancer caused by those types, wasn’t approved by the FDA when the March 2006 “Update on Cervical Disease” was published. Preapproval expectations were high at the time; what we have witnessed since approval of Gardasil (Merck) has, in fact, exceeded earlier expectations.

As of August 31, 2008, more than 20 million doses of Gardasil have been administered. A CDC survey of 3,000 US adolescents 13 to 17 years old showed that one of every four received at least one shot of the vaccine in 2007, the first full year after approval. This uptake of the HPV vaccine during its first year is significantly better than 12% for the meningococcal vaccine and 11% for Tdap in the year after their introduction.

Is the vaccine efficacious?

Recent data from Joura and colleagues, based on more than 6 years of follow-up of women immunized with the quadrivalent vaccine, have not shown any decrease in protection from CIN 3+. There has been concern, however, that falling antibody levels that have been noted, particularly against HPV type 18, may indicate reduced protection from high-grade squamous or glandular disease.

To clarify the matter, these investigators evaluated efficacy data on the 40% of vaccine subjects who were anti-HPV 18-seronegative at the end of the study. Despite the inability to document antibodies to HPV 18 in these subjects, efficacy against HPV 18-related CIN 3 or adenocarcinoma in situ remained high at 98.4% compared with the placebo group. Th ese results suggest that vaccine-induced protection is high despite lower-than-detectable anti-HPV 18 titers.

How safe is it?

The safety of the HPV vaccine was studied in seven clinical trials in more than 21,000 girls and women 9 to 26 years old before it was licensed. The conclusion was that this is a very safe vaccine. But much has been made in the media—and even in a few peer-reviewed articles in the medical literature—that nevertheless questions the safety of Gardasil, and there is little doubt that clinicians who administer the vaccine have been bombarded with questions about this by their patients.

As of August 31, 2008, there were 10,326 Vaccine Adverse Event Reporting System (VAERS) reports of adverse events following Gardasil vaccination in the United States: 94% were considered nonserious and 6% were serious. These numbers appear great, but a 6% rate of serious adverse events is only about one half of the 10% to 15% rate observed after other vaccines made their debut.

VAERS, one of three systems utilized to monitor the safety of all vaccines after licensing and marketing in the United States, is open to the public. This means that it collects data without verifying the relationship of the adverse event to the vaccine other than proximity of timing. In a joint July 2008 Web-site posting, the CDC and FDA said: “In some media reports and on some web sites on the Internet, VAERS reports are presented as verified cases of vaccine deaths and injuries. Statements such as these misrepresent the nature of VAERS surveillance system.”

As part of ongoing surveillance, the CDC met in October 2008 to review Gardasil safety data. A synopsis of findings follows.

Minor adverse events

Reports of nonserious adverse events include syncope, pain and swelling at the site of injection (the arm), headache, nausea, and fever. The most common side effect reported to VAERS is syncope.

The FDA-CDC report emphasizes that syncope as a vasovagal reaction can occur after any vaccination, particularly in an adolescent. Syncope is not serious unless the patient is injured as she falls.

Major adverse events

Of course, greatest concern over the safety of the HPV vaccine is with reports of major adverse events following administration—including death. The October 2008 FDACDC review says that careful evaluation by medical experts of all serious reports has not found a common medical pattern to suggest that any were caused by the vaccine. Here is a summary of serious adverse-event reports submitted to VAERS between June 8, 2006, and August 31, 2008.

Guillain-Barré syndrome has been reported after vaccination with Gardasil. This rare disorder occurs in 1 or 2 of every 100,000 adolescents, and can be caused by any of several infectious agents. The FDA and CDC report no indication that Gardasil increases the rate of Guillain-Barré syndrome in females above the rate expected in the general population.

Blood clots have been reported in the heart, lungs, and legs of women after vaccination with Gardasil. In most cases, thorough evaluation identified other risk factors for clotting, including use of an oral contraceptive.

Death. There have been 27 reports in the United States of death among females who have been given the vaccine. The FDA-CDC review of each case has not documented a common pattern to these deaths to suggest that the vaccine was the cause of death. Here is a breakdown of those 27 reports:

• 3 related to diabetes or heart failure
• 3 to a viral illness, including meningitis
• 2 to drug use
• 2 to blood clots
• 5 are still being evaluated
• 1 report of a seizure disorder (patient had a history of seizures)
• 11 reports in which the cause of death is: unknown; cannot be evaluated because the person’s name or the death is unverified; or is still under review while medical records are obtained.

CASE: Erratic screening history with at least 1 abnormality

G.A., 40, vaguely remembers having at least 1 abnormal Pap test about 20 years ago. She is not sure exactly what the result was, but does recall that she underwent colposcopy. Her physician at the time told her that nothing important was detected and encouraged her to get “regular Pap tests” in the future. She followed this advice for several years, but her Pap tests became much less frequent after her 2 children were born. Today, she reports that her last Pap test was at least 5 years ago, but she does not remember exactly when. She also remembers being notified that she needed to repeat it, but is not sure why. Her records are unavailable because she has moved a lot and cannot remember the name of the doctor who saw her.

Today, G.A. is screened with both a Pap test and a human papillomavirus (HPV) test for high-risk viral types. The physician outlines the benefits of doing both tests and explains the “commonness” of HPV, offering reassuring facts about its natural history to “soften the concern” in the event she is found to be positive.

The Pap test comes back as “negative for intraepithelial neoplasia or malignancy” (ie, normal), but her HPV test is positive.

What questions is G.A. likely to raise? How can her risk of cervical cancer be quantified? And how should she be managed?

Why do an HPV test with the Pap?

G.A.’s situation is not unusual. Many women provide a vague history that includes 1 or more abnormal Pap tests in the distant past, with “probably normal” results on infrequent, irregular screening in more recent years.

It has been estimated that annual lifetime screening with a Pap test sensitivity of 70% for cervical intraepithelial neoplasia (CIN) 2 or 3 reduces the lifetime risk of cervical cancer by 93%. That means that even diligent lifetime screening will leave some women unprotected.¹

The risk increases for women who are not screened regularly, especially those with a history of an abnormal Pap test. Approximately 10% of cervical cancers occur in women who have been screened in the past but not within the past 5 years.²

Pap test alone has poor sensitivity

A number of meta-analyses have documented the sensitivity of the conventional Pap smear for the detection of CIN 2,3 to be between 51% and 67%.^3,4 And although liquid-based cytology offers many advantages, early reports of improved sensitivity over conventional cytology were not substantiated in a 2006 meta-analysis of a large number of studies (as reported in Update on Cervical Disease, by Thomas C. Wright, MD, in the March issue of OBG Management).⁵

Despite the low sensitivity of cervical cytology, Pap test screening has been extremely successful in detecting precancerous cervical changes and allowing timely treatment. The success is directly attributable to repeated screening of women during the relatively slow progression from initial HPV infection to CIN 3 (typically, about 10 years) and from CIN 3 to cancer (typically, 10 or more years).⁶ Poor sensitivity raises concern, however, when screening attendance is not ideal.

Together, the tests lower the risk of missing CIN or cancer to 1 in 1,000

Surely, G.A. would benefit by having the most reassuring screening available. Guidelines from the American Cancer Society (2002) and 2 practice bulletins from the American College of Obstetricians and Gynecologists (ACOG) (2003, 2005) recommend as 1 of 2 options screening women age 30 and over with both the Pap test and the HPV test for high-risk types. ^7-9

A 2005 ACOG practice bulletin on HPV¹⁰ noted the reassurance offered by combined testing and observed that, based on Level A evidence, “HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, [so] women with concurrent negative test results can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000.”

Most women would benefit from a screening test that provides a reassurance of 1 in 1,000. Given G.A.’s infrequent screening history, previous abnormal cervical cytology, and unknown result on her last screen over 5 years ago, using the most reassuring combination of tests would seem to be imperative.

Likely questions

Because HPV testing plays an ever-increasing role in cervical screening, it presents a new set of educational challenges.⁶ Until recently, clinicians generally avoided discussing the cause of abnormal cervical cytology, CIN, and cervical cancer. However, when a woman is tested for high-risk HPV along with the Pap test in primary screening, the subject can no longer be skirted. Already the HPV vaccine and widespread use of the Web by patients have changed the information base on HPV. Education can begin at the time of the Pap and HPV tests, need not be extensive, and often can deflect undue anxiety and many of the patient’s questions about a positive result.

G.A. has been married for nearly 22 years. Her husband has been her only partner, but he was sexually active before they were married. She is naturally concerned about how long she has had HPV and what this means for her relationship. Her questions are universal: How and when did I become infected? What is my risk and that of my partner? How will I be managed? Will I always have HPV?

These questions may seem daunting, but the answers can be kept simple and short and still provide enough information to be reassuring and to prepare the patient for a possible positive test result.

Quantify risk before you select management

Most women with normal cytology but a first-time positive HPV test do not have CIN 2,3 or greater.^11-14 A National Cancer Institute prospective 10-year follow-up of more than 20,000 women screened at enrollment with both the HPV test and cytology demonstrated that only 4.4% of the HPV-positive, Pap-negative women had CIN 3 or cancer detected over the following 3 to 5 years, and only 7% did by 10 years.^13,14 These rates are similar to those found in other studies and are about half the risk represented by a Pap result of atypical squamous cells of undetermined significance (ASC-US).¹⁵

Therefore, because of the low immediate risk for high-grade cervical neoplasia and the extremely rare occurrence of cervical cancer in this setting, immediate referral to colposcopy is not recommended in routine cases (FIGURE 1).^9,15 Instead, repeating Pap and HPV testing in 6 to 12 months yields a more accurate picture of risk by determining whether the HPV is only transient or is persistent. Only persistent HPV is associated with significant risk for CIN 2,3. Therefore, repeating the tests, rather than sending the patient to immediate colposcopy, allows the 45% to 70% of HPV infections destined to be transient to resolve spontaneously, but will still detect most significant lesions within a reasonable period of time.¹⁵

FIGURE 1 How to interpret the HPV test and cytology combined: NCI–ASCCP Interim Guidance
SOURCE: National Cancer Institute and the American Society for Colposcopy and Cervical Pathology. Adapted from Wright et al¹⁵
ASC-US=atypical squamous cells of undetermined significance; HPV=human papillomavirus; LSIL=low-grade squamous intraepithelial lesions.If G.A. is managed in this way and, at the 6- and 12-month repeats of both tests, has a positive HPV test (regardless of the cytology finding) or any abnormal Pap test result other than HPV-negative/ASC-US, she should undergo colposcopy.¹⁵ A test designated as HPV-negative/ASC-US can be managed by repeat testing in 12 months.

Remember: Even though a repeat positive HPV test increases the patient’s risk of CIN 2,3 significantly, it is specifically not recommended to treat the cervix solely on the basis of a persistently positive HPV test without evidence of CIN or cervical cancer.

This patient warrants a different approach—here’s why

Although repeat Pap and HPV testing in 6 to 12 months is the standard recommendation for women with a normal Pap test and positive HPV results, extenuating circumstances may exist. Clinical judgment always trumps routine recommendations in these cases.

The progression of CIN 3 to cervical cancer is usually a slow process that occurs over many years.⁶ Therefore, delaying colposcopy for 6 to 12 months will probably not increase risk significantly even if a high-grade lesion is already present. But G.A.’s case involves a number of variables that may increase her risk enough to justify immediate colposcopy:

• an abnormal Pap test more than 20 years ago
• a history of irregular screening
• no screening within the past 5 years until the current testing
• concern that her last Pap result was either minimally abnormal or of limited quality.

Lack of access to any earlier records further limits the physician’s ability to adequately judge G.A.’s risk. Because of these concerns, the physician asks G.A. to come in for colposcopy, at which time a 2-quadrant CIN 3 lesion is found (FIGURE 2). The patient is treated by loop electrosurgical excision procedure and has normal cytology and a negative HPV test result on follow-up.

FIGURE 2 Two-quadrant CIN 2,3

High-grade lesions begin as a monoclonal cell change that enlarges centrifugally. Hence, increasing size is suspect for increasing duration of presence and increasing risk for cancer, because risk of invasion is proportional to lesion size.

The author reports no financial relationships relevant to this article.

CASE: Erratic screening history with at least 1 abnormality

G.A., 40, vaguely remembers having at least 1 abnormal Pap test about 20 years ago. She is not sure exactly what the result was, but does recall that she underwent colposcopy. Her physician at the time told her that nothing important was detected and encouraged her to get “regular Pap tests” in the future. She followed this advice for several years, but her Pap tests became much less frequent after her 2 children were born. Today, she reports that her last Pap test was at least 5 years ago, but she does not remember exactly when. She also remembers being notified that she needed to repeat it, but is not sure why. Her records are unavailable because she has moved a lot and cannot remember the name of the doctor who saw her.

Today, G.A. is screened with both a Pap test and a human papillomavirus (HPV) test for high-risk viral types. The physician outlines the benefits of doing both tests and explains the “commonness” of HPV, offering reassuring facts about its natural history to “soften the concern” in the event she is found to be positive.

The Pap test comes back as “negative for intraepithelial neoplasia or malignancy” (ie, normal), but her HPV test is positive.

What questions is G.A. likely to raise? How can her risk of cervical cancer be quantified? And how should she be managed?

Why do an HPV test with the Pap?

G.A.’s situation is not unusual. Many women provide a vague history that includes 1 or more abnormal Pap tests in the distant past, with “probably normal” results on infrequent, irregular screening in more recent years.

It has been estimated that annual lifetime screening with a Pap test sensitivity of 70% for cervical intraepithelial neoplasia (CIN) 2 or 3 reduces the lifetime risk of cervical cancer by 93%. That means that even diligent lifetime screening will leave some women unprotected.¹

The risk increases for women who are not screened regularly, especially those with a history of an abnormal Pap test. Approximately 10% of cervical cancers occur in women who have been screened in the past but not within the past 5 years.²

Pap test alone has poor sensitivity

A number of meta-analyses have documented the sensitivity of the conventional Pap smear for the detection of CIN 2,3 to be between 51% and 67%.^3,4 And although liquid-based cytology offers many advantages, early reports of improved sensitivity over conventional cytology were not substantiated in a 2006 meta-analysis of a large number of studies (as reported in Update on Cervical Disease, by Thomas C. Wright, MD, in the March issue of OBG Management).⁵

Despite the low sensitivity of cervical cytology, Pap test screening has been extremely successful in detecting precancerous cervical changes and allowing timely treatment. The success is directly attributable to repeated screening of women during the relatively slow progression from initial HPV infection to CIN 3 (typically, about 10 years) and from CIN 3 to cancer (typically, 10 or more years).⁶ Poor sensitivity raises concern, however, when screening attendance is not ideal.

Together, the tests lower the risk of missing CIN or cancer to 1 in 1,000

Surely, G.A. would benefit by having the most reassuring screening available. Guidelines from the American Cancer Society (2002) and 2 practice bulletins from the American College of Obstetricians and Gynecologists (ACOG) (2003, 2005) recommend as 1 of 2 options screening women age 30 and over with both the Pap test and the HPV test for high-risk types. ^7-9

A 2005 ACOG practice bulletin on HPV¹⁰ noted the reassurance offered by combined testing and observed that, based on Level A evidence, “HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, [so] women with concurrent negative test results can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000.”

Most women would benefit from a screening test that provides a reassurance of 1 in 1,000. Given G.A.’s infrequent screening history, previous abnormal cervical cytology, and unknown result on her last screen over 5 years ago, using the most reassuring combination of tests would seem to be imperative.

Likely questions

Because HPV testing plays an ever-increasing role in cervical screening, it presents a new set of educational challenges.⁶ Until recently, clinicians generally avoided discussing the cause of abnormal cervical cytology, CIN, and cervical cancer. However, when a woman is tested for high-risk HPV along with the Pap test in primary screening, the subject can no longer be skirted. Already the HPV vaccine and widespread use of the Web by patients have changed the information base on HPV. Education can begin at the time of the Pap and HPV tests, need not be extensive, and often can deflect undue anxiety and many of the patient’s questions about a positive result.

G.A. has been married for nearly 22 years. Her husband has been her only partner, but he was sexually active before they were married. She is naturally concerned about how long she has had HPV and what this means for her relationship. Her questions are universal: How and when did I become infected? What is my risk and that of my partner? How will I be managed? Will I always have HPV?

These questions may seem daunting, but the answers can be kept simple and short and still provide enough information to be reassuring and to prepare the patient for a possible positive test result.

Quantify risk before you select management

Most women with normal cytology but a first-time positive HPV test do not have CIN 2,3 or greater.^11-14 A National Cancer Institute prospective 10-year follow-up of more than 20,000 women screened at enrollment with both the HPV test and cytology demonstrated that only 4.4% of the HPV-positive, Pap-negative women had CIN 3 or cancer detected over the following 3 to 5 years, and only 7% did by 10 years.^13,14 These rates are similar to those found in other studies and are about half the risk represented by a Pap result of atypical squamous cells of undetermined significance (ASC-US).¹⁵

Therefore, because of the low immediate risk for high-grade cervical neoplasia and the extremely rare occurrence of cervical cancer in this setting, immediate referral to colposcopy is not recommended in routine cases (FIGURE 1).^9,15 Instead, repeating Pap and HPV testing in 6 to 12 months yields a more accurate picture of risk by determining whether the HPV is only transient or is persistent. Only persistent HPV is associated with significant risk for CIN 2,3. Therefore, repeating the tests, rather than sending the patient to immediate colposcopy, allows the 45% to 70% of HPV infections destined to be transient to resolve spontaneously, but will still detect most significant lesions within a reasonable period of time.¹⁵

FIGURE 1 How to interpret the HPV test and cytology combined: NCI–ASCCP Interim Guidance
SOURCE: National Cancer Institute and the American Society for Colposcopy and Cervical Pathology. Adapted from Wright et al¹⁵
ASC-US=atypical squamous cells of undetermined significance; HPV=human papillomavirus; LSIL=low-grade squamous intraepithelial lesions.If G.A. is managed in this way and, at the 6- and 12-month repeats of both tests, has a positive HPV test (regardless of the cytology finding) or any abnormal Pap test result other than HPV-negative/ASC-US, she should undergo colposcopy.¹⁵ A test designated as HPV-negative/ASC-US can be managed by repeat testing in 12 months.

Remember: Even though a repeat positive HPV test increases the patient’s risk of CIN 2,3 significantly, it is specifically not recommended to treat the cervix solely on the basis of a persistently positive HPV test without evidence of CIN or cervical cancer.

This patient warrants a different approach—here’s why

Although repeat Pap and HPV testing in 6 to 12 months is the standard recommendation for women with a normal Pap test and positive HPV results, extenuating circumstances may exist. Clinical judgment always trumps routine recommendations in these cases.

The progression of CIN 3 to cervical cancer is usually a slow process that occurs over many years.⁶ Therefore, delaying colposcopy for 6 to 12 months will probably not increase risk significantly even if a high-grade lesion is already present. But G.A.’s case involves a number of variables that may increase her risk enough to justify immediate colposcopy:

• an abnormal Pap test more than 20 years ago
• a history of irregular screening
• no screening within the past 5 years until the current testing
• concern that her last Pap result was either minimally abnormal or of limited quality.

Lack of access to any earlier records further limits the physician’s ability to adequately judge G.A.’s risk. Because of these concerns, the physician asks G.A. to come in for colposcopy, at which time a 2-quadrant CIN 3 lesion is found (FIGURE 2). The patient is treated by loop electrosurgical excision procedure and has normal cytology and a negative HPV test result on follow-up.

FIGURE 2 Two-quadrant CIN 2,3

High-grade lesions begin as a monoclonal cell change that enlarges centrifugally. Hence, increasing size is suspect for increasing duration of presence and increasing risk for cancer, because risk of invasion is proportional to lesion size.

The author reports no financial relationships relevant to this article.

CASE: Erratic screening history with at least 1 abnormality

G.A., 40, vaguely remembers having at least 1 abnormal Pap test about 20 years ago. She is not sure exactly what the result was, but does recall that she underwent colposcopy. Her physician at the time told her that nothing important was detected and encouraged her to get “regular Pap tests” in the future. She followed this advice for several years, but her Pap tests became much less frequent after her 2 children were born. Today, she reports that her last Pap test was at least 5 years ago, but she does not remember exactly when. She also remembers being notified that she needed to repeat it, but is not sure why. Her records are unavailable because she has moved a lot and cannot remember the name of the doctor who saw her.

Today, G.A. is screened with both a Pap test and a human papillomavirus (HPV) test for high-risk viral types. The physician outlines the benefits of doing both tests and explains the “commonness” of HPV, offering reassuring facts about its natural history to “soften the concern” in the event she is found to be positive.

The Pap test comes back as “negative for intraepithelial neoplasia or malignancy” (ie, normal), but her HPV test is positive.

What questions is G.A. likely to raise? How can her risk of cervical cancer be quantified? And how should she be managed?

Why do an HPV test with the Pap?

G.A.’s situation is not unusual. Many women provide a vague history that includes 1 or more abnormal Pap tests in the distant past, with “probably normal” results on infrequent, irregular screening in more recent years.

It has been estimated that annual lifetime screening with a Pap test sensitivity of 70% for cervical intraepithelial neoplasia (CIN) 2 or 3 reduces the lifetime risk of cervical cancer by 93%. That means that even diligent lifetime screening will leave some women unprotected.¹

The risk increases for women who are not screened regularly, especially those with a history of an abnormal Pap test. Approximately 10% of cervical cancers occur in women who have been screened in the past but not within the past 5 years.²

Pap test alone has poor sensitivity

A number of meta-analyses have documented the sensitivity of the conventional Pap smear for the detection of CIN 2,3 to be between 51% and 67%.^3,4 And although liquid-based cytology offers many advantages, early reports of improved sensitivity over conventional cytology were not substantiated in a 2006 meta-analysis of a large number of studies (as reported in Update on Cervical Disease, by Thomas C. Wright, MD, in the March issue of OBG Management).⁵

Despite the low sensitivity of cervical cytology, Pap test screening has been extremely successful in detecting precancerous cervical changes and allowing timely treatment. The success is directly attributable to repeated screening of women during the relatively slow progression from initial HPV infection to CIN 3 (typically, about 10 years) and from CIN 3 to cancer (typically, 10 or more years).⁶ Poor sensitivity raises concern, however, when screening attendance is not ideal.

Together, the tests lower the risk of missing CIN or cancer to 1 in 1,000

Surely, G.A. would benefit by having the most reassuring screening available. Guidelines from the American Cancer Society (2002) and 2 practice bulletins from the American College of Obstetricians and Gynecologists (ACOG) (2003, 2005) recommend as 1 of 2 options screening women age 30 and over with both the Pap test and the HPV test for high-risk types. ^7-9

A 2005 ACOG practice bulletin on HPV¹⁰ noted the reassurance offered by combined testing and observed that, based on Level A evidence, “HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, [so] women with concurrent negative test results can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000.”

Most women would benefit from a screening test that provides a reassurance of 1 in 1,000. Given G.A.’s infrequent screening history, previous abnormal cervical cytology, and unknown result on her last screen over 5 years ago, using the most reassuring combination of tests would seem to be imperative.

Likely questions

Because HPV testing plays an ever-increasing role in cervical screening, it presents a new set of educational challenges.⁶ Until recently, clinicians generally avoided discussing the cause of abnormal cervical cytology, CIN, and cervical cancer. However, when a woman is tested for high-risk HPV along with the Pap test in primary screening, the subject can no longer be skirted. Already the HPV vaccine and widespread use of the Web by patients have changed the information base on HPV. Education can begin at the time of the Pap and HPV tests, need not be extensive, and often can deflect undue anxiety and many of the patient’s questions about a positive result.

G.A. has been married for nearly 22 years. Her husband has been her only partner, but he was sexually active before they were married. She is naturally concerned about how long she has had HPV and what this means for her relationship. Her questions are universal: How and when did I become infected? What is my risk and that of my partner? How will I be managed? Will I always have HPV?

These questions may seem daunting, but the answers can be kept simple and short and still provide enough information to be reassuring and to prepare the patient for a possible positive test result.

Quantify risk before you select management

Most women with normal cytology but a first-time positive HPV test do not have CIN 2,3 or greater.^11-14 A National Cancer Institute prospective 10-year follow-up of more than 20,000 women screened at enrollment with both the HPV test and cytology demonstrated that only 4.4% of the HPV-positive, Pap-negative women had CIN 3 or cancer detected over the following 3 to 5 years, and only 7% did by 10 years.^13,14 These rates are similar to those found in other studies and are about half the risk represented by a Pap result of atypical squamous cells of undetermined significance (ASC-US).¹⁵

Therefore, because of the low immediate risk for high-grade cervical neoplasia and the extremely rare occurrence of cervical cancer in this setting, immediate referral to colposcopy is not recommended in routine cases (FIGURE 1).^9,15 Instead, repeating Pap and HPV testing in 6 to 12 months yields a more accurate picture of risk by determining whether the HPV is only transient or is persistent. Only persistent HPV is associated with significant risk for CIN 2,3. Therefore, repeating the tests, rather than sending the patient to immediate colposcopy, allows the 45% to 70% of HPV infections destined to be transient to resolve spontaneously, but will still detect most significant lesions within a reasonable period of time.¹⁵

FIGURE 1 How to interpret the HPV test and cytology combined: NCI–ASCCP Interim Guidance
SOURCE: National Cancer Institute and the American Society for Colposcopy and Cervical Pathology. Adapted from Wright et al¹⁵
ASC-US=atypical squamous cells of undetermined significance; HPV=human papillomavirus; LSIL=low-grade squamous intraepithelial lesions.If G.A. is managed in this way and, at the 6- and 12-month repeats of both tests, has a positive HPV test (regardless of the cytology finding) or any abnormal Pap test result other than HPV-negative/ASC-US, she should undergo colposcopy.¹⁵ A test designated as HPV-negative/ASC-US can be managed by repeat testing in 12 months.

Remember: Even though a repeat positive HPV test increases the patient’s risk of CIN 2,3 significantly, it is specifically not recommended to treat the cervix solely on the basis of a persistently positive HPV test without evidence of CIN or cervical cancer.

This patient warrants a different approach—here’s why

Although repeat Pap and HPV testing in 6 to 12 months is the standard recommendation for women with a normal Pap test and positive HPV results, extenuating circumstances may exist. Clinical judgment always trumps routine recommendations in these cases.

The progression of CIN 3 to cervical cancer is usually a slow process that occurs over many years.⁶ Therefore, delaying colposcopy for 6 to 12 months will probably not increase risk significantly even if a high-grade lesion is already present. But G.A.’s case involves a number of variables that may increase her risk enough to justify immediate colposcopy:

• an abnormal Pap test more than 20 years ago
• a history of irregular screening
• no screening within the past 5 years until the current testing
• concern that her last Pap result was either minimally abnormal or of limited quality.

Lack of access to any earlier records further limits the physician’s ability to adequately judge G.A.’s risk. Because of these concerns, the physician asks G.A. to come in for colposcopy, at which time a 2-quadrant CIN 3 lesion is found (FIGURE 2). The patient is treated by loop electrosurgical excision procedure and has normal cytology and a negative HPV test result on follow-up.

FIGURE 2 Two-quadrant CIN 2,3

High-grade lesions begin as a monoclonal cell change that enlarges centrifugally. Hence, increasing size is suspect for increasing duration of presence and increasing risk for cancer, because risk of invasion is proportional to lesion size.

The author reports no financial relationships relevant to this article.

It could be the end of the affair with HPV!¹ With this exclamation, Prof. Margaret Stanley, the noted human papillomavirus immunologist, expressed the optimism we all share, now that the possibility of conquering cervical cancer is within view. Not yet 25 years have passed since the first sequencing of a genital HPV type, and scarcely 10 years since the International Agency for Research on Cancer proclaimed that HPV causes cervical cancer. It has been 57 years since the discovery that launched an international quest to reduce the cervical cancer rate: George Papanicolaou’s test for early abnormal cell changes that, decades later, were found to be secondary to HPV. We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality.

But even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. And the Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab and country to country.

What is new in 2006 that we may soon be able to put into practice, bringing us closer to a new world—with respect to cervical cancer prevention—different from any we’ve known?

• 1 More sensitive and objective screening
• 2 Better management of screen positives
• 3 HPV vaccine, soon to be in our offices

1 More sensitive and more objective screening

A comforting combo: Negative Pap and HPV tests

ACOG Practice Bulletin, Number 61. Human papillomavirus. Washington, DC: American College of Obstetricians and Gynecologists; April 2005.

Because HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, women with concurrent negative Pap and HPV tests can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000. (Level A evidence)

The American Cancer Society and the American College of Obstetricians and Gynecologists have both provided as an option the screening of women age 30 and older with the combination of the Pap and a test for high-risk HPV types.^2,3 These “sophisticated new tests for the detection of HPV…hold great promise for improved screening for cervical cancer precursors and invasive cancer, and for triage of cervical cytology,” the Bulletin states.

Not all women get annual screening, however, and even if they do, the IARC estimates, the lifetime risk for cervical cancer for women who have conventional Paps annually is approximately 216 per 100,000, if the Pap sensitivity is about 70%. The prospect of reducing the risk of missing significant cervical neoplasia at each screen to 1 per 1,000 should be of comfort to women and the clinicians who watch over their health.

Dilemma: Women over 30, with normal Pap and high-risk HPV

What about the approximately 4% of women aged 30 and older with normal cytology and high-risk HPV? How should these women be managed? A panel of experts on HPV and cervical screening published “interim guidance” in 2004, recommending that until further data are available, these women should be retested in 6 to 12 months for persistence of HPV or development of abnormal cytology, and referred to colposcopy if still HPV-positive or if Pap results show low-grade squamous intraepithelial lesion (LSIL) or worse, regardless of HPV result.⁴

Although the April 2005 ACOG Bulletin affirmed that guideline, concern persisted that, while some women so identified might be better evaluated immediately by colposcopy, the majority would not, and there was no good way to identify HPV-positive women most at risk. Several longitudinal studies (discussed in the following section) have now made the path clearer.

REFERENCES

1. Stanley M. The end for genital human papillomavirus infections? Lancet Oncol 2005;6:256-257.

2. Sasow D, Runowicz CD, Solomon D, et al, for the American Cancer Society. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52:342-362.

3. ACOG Practice Bulletin, Number 45. Cervical cytology screening. Washington, DC: American College of Obstetricians and Gynecologists; 2003.

4. 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;103:304-309.

Type-specific testing identifies highest risk

Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–1079.

HPV screening that distinguishes types 16 and 18 from other oncogenic (high-risk) HPV types identifies women at the greatest risk of CIN 2/3+ and may permit less aggressive management of women with other high-risk HPV infections.

The solution to the dilemma of having to wait 6 to 12 months to repeat Pap and HPV tests for women with a normal cytology but a positive HPV test before determining the need for colposcopy may be solved by type-specific HPV testing. The 10-year cumulative incidence of CIN 3 and cervical cancer (CIN 3+) in 20,810 women tested once for HPV at enrollment was only 0.8% in the women who tested negative for high-risk HPV by Hybrid Capture 2. In contrast, CIN 3+ developed in 17% of the HPV-16-positive women and 14% of the HPV-18-positive women within 10 years.

Women positive for other high-risk types of HPV, but negative for HPV 16 and 18 had far less risk: only 3% developed CIN 3+.

When stratified by age to limit the analysis to women aged 30 and older, the cumulative incidence of CIN 3+ was 20% in HPV-16-positive women and 15% in HPV-18-positive women (FIGURE 1). Contrast these results to the 10-year predictive value of 11% for an LSIL Pap for the same level of cervical neoplasia. In other words, a single positive HPV 16 or 18 test is almost twice as likely to identify women at high risk for CIN 3+ as an LSIL Pap result, over time.

FIGURE 1 Positive HPV 16 or 18 linked to 14% to 17% incidence of CIN3+

The cumulative incidence of CIN 3+ over a 10-year period, as a function of a single HPV test result at enrollment. Women positive for HPV 16 or 18 had a much greater incidence of CIN 3+, compared to women negative for HPV 16 and 18 but positive for other high-risk HPV types by Hybrid Capture 2, or negative for all high-risk HPV types. Adapted from Khan et al.

Follow-up according to risk

These findings support a follow-up strategy that would permit risk stratification of HPV-infected women for whom an optimal repeat screening interval has been unclear.

• Women positive for HPV 16 or 18 warrant referral to colposcopy, for they carry the majority of risk from a positive high-risk HPV test.
• Women positive only for other high-risk types could be reassured of the safety of a 12-month interval without colposcopy, and referred to colposcopy only if the repeat Pap shows worse than atypical squamous cells of undetermined significance (ASC-US) or the HPV test is again positive (FIGURE 2).

FIGURE 2 Type-specific testing in clinical practice

Proposed management of women aged 30 or older, who are screened concurrently with both a Pap test and an HPV test, with typing for HPV 16/18. Adapted from Khan et al.

2 type-specific tests in the pipeline

Currently, the only FDA-approved test for combined screening of women aged 30 and older is the Hybrid Capture 2 High-risk HPV test, which tests for a panel of the 13 most common HPV types known to cause cervical cancer, but does not report on individual types.

But 2 type-specific HPV tests may become available in 2006, which would enable clinicians to follow this strategy.

Digene is nearly ready to launch a 16, 18, 45 type-specific “reflex” test (to a positive Hybrid Capture 2 HPV panel), and Roche is preparing to get its type-specific Linear Array HPV test approved.

2 Better management of screen positives

New practice bulletin on managing abnormal tests

ACOG Practice Bulletin, Number 66. Management of abnormal cervical cytology and histology. Washington, DC: American College of Obstetricians and Gynecologists; September 2005.

The new Practice Bulletin published last September in most respects mirrors the most recent American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus guidelines.¹

Key points

• ASC-US may be managed by referral to immediate colposcopy, by repeat Pap, or by HPV testing. However, “reflex HPV testing” when ASC-US is derived from liquid-based cytology has advantages. (It is estimated that a large majority of ASC-US is now managed by HPV testing.)
• Initial management of all other Pap abnormalities is by immediate referral to colposcopy, ie, the finding of atypical squamous cells cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), LSIL, and high-grade intraepithelial lesions (HSIL).
• Management of ASC-US and LSIL in adolescence and postmenopause: ACOG provides an alternative strategy for adolescents with either ASC-US or LSIL cytology, who may have either repeat cytology at 6 and 12 months or a single HPV test at 12 months. ACOG did not differentiate postmenopausal women with either ASC-US or LSIL as “special situations” with additional management strategies.
• CIN 2/3 should usually be treated, both guidelines say. The only exception is the adolescent with CIN 2, who may be followed with repeat cytology and colposcopy at 4 to 6 months if she is deemed reliable for follow-up, the colposcopy is adequate, and the endocervical sampling is negative.
• HPV-positive ASC-US, ASC-H, or LSIL and either CIN 1 or normal colposcopy findings should be followed by repeat Pap at 6 and 12 months, or a single HPV test at 12 months, with referral to colposcopy if either the Pap results show ASC-US or more advanced abnormality or the HPV test is positive.
• In contrast, an excisional procedure is required for normal findings, or an unsatisfactory colposcopy in nonpregnant women referred for atypical glandular cells “favor neoplasia” (AGC-H), or adenocarcinoma in situ (AIS), or repeat atypical glandular cells “not otherwise specified” (AGC-NOS), or HSIL. The only exception is an adolescent with HSIL cytology and a satisfactory and normal colposcopy and biopsy, who may be followed closely.
• Women treated for CIN 2/3 can be monitored after treatment by cytology screening at 6-month intervals 3 or 4 times or by a single HPV test at 6 months, before returning to annual screening. Any repeat abnormal Pap at the threshold of ASC-US or more advanced abnormality or a positive HPV test requires colposcopic evaluation.

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. American Society for Colposcopy and Cervical Pathology. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

3 HPV vaccine, soon to be in our offices

Vaccines will stop CIN 2/3 and cancer

Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107:18–27.

The HPV 16 vaccine provided 100% protection against development of HPV-16-related CIN 2/3 during an average of 3.5 years of follow-up.

This preliminary study to the Quadrivalent HPV 6, 11, 16, 18 trial on an HPV 16 virus-like particle (VLP) vaccine reached an average of 3.5 years of follow-up. CIN 2/3 developed in 12 of the 750 women receiving placebo, in contrast to none of the 755 vaccine recipients. Persistent HPV 16 infections were defined as testing positive for type-specific HPV 16 on 2 or more visits, with the caveat that women testing positive on the last visit were considered persistent because they would have no further follow-up to determine that status. As a result, some women with a positive test only on the last visit were included as “persisters,” perhaps explaining why the efficacy in preventing persistent HPV 16 in the vaccine recipients was only 94%. Single-test positives can be transient infections, vaginal contamination with infected cells from a partner during recent intercourse, or early persistent infections. Although antibody titers to HPV 16 in vaccine recipients waned over time, they still exceeded titers in placebo recipients who already had natural immunity to HPV 16.

Benefit of the HPV 16 vaccine was also seen for women already HPV-16 positive at enrollment, but only if they were seronegative for HPV 16. It is possible that, if an immune response has not yet been mounted, the vaccine may still have a positive effect for women already HPV-16 infected.

Who will be vaccinated?

Although the primary target group for the HPV vaccine will be children before natural exposure can occur after the onset of sexual activity, many women already sexually active will likely want to be vaccinated.

It is this “catch-up” group that will challenge the OBGyn to become familiar with and to provide the HPV vaccine when it becomes available, likely later this year.

Quadrivalent vaccine 100% effective

Skjeldstad FE, Koutsky LA, for the Merck Phase 3 HPV Vaccine Steering Committee (Future II). Phase II trial of prophylactic quadrivalent HPV 6, 11, 16, 18 L1 virus-like particle (VLP) vaccine; prevention of cervical intraepithelial neoplasia (CIN) 2/3 including adeno- and squamous cell carcinoma in situ (CIS). Presented at: Infectious Diseases Society of America, Late Breaker Session 66, LB–8A; October 7, 2005; San Francisco, Calif.

The Quadrivalent HPV 6, 11, 16, 18 vaccine provided 100% protection against persistent HPV 16/18 and HPV 16/18-related CIN 2/3.

This trial became center stage in the world media in early October 2005, with headlines such as “First anti-cancer vaccine 100% effective.” The results are truly astounding, as there were no CIN 2/3 cases in the Per Protocol group, among the 5,301 women vaccinated, in contrast to 21 cases in the 5,258 women who received the placebo (TABLE 1).

In the group most likely to mirror a typical vaccinated population, only 1 case of HPV-16/18-positive CIN 2/3 occurred in the 5,736 vaccinated women, some of whom were already positive for 1 or more HPV types, or had serologic evidence of prior type-specific infection, or received fewer than the 3 recommended doses. In contrast, 36 HPV-16/18 CIN 2/3 occurred in the 5,766 women who received placebo.

TABLE 1

Efficacy of quadrivalent HPV 6, 11, 16, 18 vaccine in preventing CIN 2/3

No warts, either

Subsequent analysis revealed similar protection from HPV 6 or 11 genital warts.

No serious adverse events were recorded in the entire trial.

Because HPV 16 and 18 together cause approximately 70% of all cervical cancers, and HPV 6 and 11 cause 90% of genital warts, these results are surely something about which to rejoice!

Gardasil and Cervarix vaccines

Now the challenge will be in getting the population vaccinated. Merck is expected to have its Gardasil Quadrivalent vaccine on the market mid- to late 2006. GlaxoSmithKline expects to put Cervarix Bivalent HPV 16, 18 vaccine on the market sometime in 2007.

How HPV vaccine will—and won’t—change practice

Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine. 2005;23:2388–2394.

Cervical screening will continue, but will be more accurate and more efficient.

Yes, we are on the verge of the possibility of reducing the risk of cervical cancer to close to zero, but it will take decades. Vaccinating young girls will not significantly reduce cervical cancer rates until these girls reach the median ages of microinvasive (early 40s) and invasive (late 40s) cervical cancer.

Even then, cervical cancer rates will depend on these factors:

• the extent of vaccination coverage
• the number of high-risk HPV types in the vaccine
• whether vaccination provides multidecade protection or falls off with time
• whether the medical community and the public continue to diligently follow recommended screening guidelines

If immune protection falls with time, booster HPV vaccine shots should provide ongoing protection, but population protection will depend on the percent of the population obtaining the booster. If the population becomes complacent about cervical screening as risk for cervical cancer decreases, then cancers will develop that would have otherwise been prevented.

Why screening will continue

Virus-like particle (VLP) vaccines for all of the important oncogenic HPV types could, theoretically, be produced. But until long after multivalent HPV vaccines that include all the important oncogenic types are available, women will require screening to prevent the 30% of cancers that occur from other high-risk HPV types not in the present vaccine. And, we will need screening to protect women who are not vaccinated, and those already infected.

As Franco and Harper stressed, “Although the future seems bright on the vaccine front, policy makers are strongly cautioned to avoid scaling back cervical cancer screening. Any premature relaxation of cervical cancer control measures already in place will bring a resurgence of the disease to the unacceptable levels of the not too distant past.”

In other words, cervical screening will continue for the foreseeable future.

A peek at a “new world”

Fewer abnormal Pap tests. The vaccine will likely steadily decrease the rate of abnormal Paps that are important, as an increasing proportion of women are vaccinated against the 2 most common types in high-grade CIN.

Colposcopies and cervical treatments will decline in number coincident with the proportion of the population vaccinated.

A training challenge? This change will decrease the number of significant lesions that a colposcopist may see, increasing the challenge of training and maintaining expertise in identification and treatment of these lesions. As significant Pap abnormalities decrease, maintaining expertise in cytologic interpretation, and even in maintaining attention to detail, may become more difficult.

Specific testing. Finding women with significant abnormalities may more and more be accomplished with the accuracy afforded by testing for specific HPV types known to be most at-risk for CIN 3+.

With respect to cervical cancer prevention, the years to come will surely be a new world, different from what we all have known.

It could be the end of the affair with HPV!¹ With this exclamation, Prof. Margaret Stanley, the noted human papillomavirus immunologist, expressed the optimism we all share, now that the possibility of conquering cervical cancer is within view. Not yet 25 years have passed since the first sequencing of a genital HPV type, and scarcely 10 years since the International Agency for Research on Cancer proclaimed that HPV causes cervical cancer. It has been 57 years since the discovery that launched an international quest to reduce the cervical cancer rate: George Papanicolaou’s test for early abnormal cell changes that, decades later, were found to be secondary to HPV. We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality.

But even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. And the Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab and country to country.

What is new in 2006 that we may soon be able to put into practice, bringing us closer to a new world—with respect to cervical cancer prevention—different from any we’ve known?

• 1 More sensitive and objective screening
• 2 Better management of screen positives
• 3 HPV vaccine, soon to be in our offices

1 More sensitive and more objective screening

A comforting combo: Negative Pap and HPV tests

ACOG Practice Bulletin, Number 61. Human papillomavirus. Washington, DC: American College of Obstetricians and Gynecologists; April 2005.

Because HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, women with concurrent negative Pap and HPV tests can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000. (Level A evidence)

The American Cancer Society and the American College of Obstetricians and Gynecologists have both provided as an option the screening of women age 30 and older with the combination of the Pap and a test for high-risk HPV types.^2,3 These “sophisticated new tests for the detection of HPV…hold great promise for improved screening for cervical cancer precursors and invasive cancer, and for triage of cervical cytology,” the Bulletin states.

Not all women get annual screening, however, and even if they do, the IARC estimates, the lifetime risk for cervical cancer for women who have conventional Paps annually is approximately 216 per 100,000, if the Pap sensitivity is about 70%. The prospect of reducing the risk of missing significant cervical neoplasia at each screen to 1 per 1,000 should be of comfort to women and the clinicians who watch over their health.

Dilemma: Women over 30, with normal Pap and high-risk HPV

What about the approximately 4% of women aged 30 and older with normal cytology and high-risk HPV? How should these women be managed? A panel of experts on HPV and cervical screening published “interim guidance” in 2004, recommending that until further data are available, these women should be retested in 6 to 12 months for persistence of HPV or development of abnormal cytology, and referred to colposcopy if still HPV-positive or if Pap results show low-grade squamous intraepithelial lesion (LSIL) or worse, regardless of HPV result.⁴

Although the April 2005 ACOG Bulletin affirmed that guideline, concern persisted that, while some women so identified might be better evaluated immediately by colposcopy, the majority would not, and there was no good way to identify HPV-positive women most at risk. Several longitudinal studies (discussed in the following section) have now made the path clearer.

REFERENCES

1. Stanley M. The end for genital human papillomavirus infections? Lancet Oncol 2005;6:256-257.

2. Sasow D, Runowicz CD, Solomon D, et al, for the American Cancer Society. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52:342-362.

3. ACOG Practice Bulletin, Number 45. Cervical cytology screening. Washington, DC: American College of Obstetricians and Gynecologists; 2003.

4. 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;103:304-309.

Type-specific testing identifies highest risk

Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–1079.

HPV screening that distinguishes types 16 and 18 from other oncogenic (high-risk) HPV types identifies women at the greatest risk of CIN 2/3+ and may permit less aggressive management of women with other high-risk HPV infections.

The solution to the dilemma of having to wait 6 to 12 months to repeat Pap and HPV tests for women with a normal cytology but a positive HPV test before determining the need for colposcopy may be solved by type-specific HPV testing. The 10-year cumulative incidence of CIN 3 and cervical cancer (CIN 3+) in 20,810 women tested once for HPV at enrollment was only 0.8% in the women who tested negative for high-risk HPV by Hybrid Capture 2. In contrast, CIN 3+ developed in 17% of the HPV-16-positive women and 14% of the HPV-18-positive women within 10 years.

Women positive for other high-risk types of HPV, but negative for HPV 16 and 18 had far less risk: only 3% developed CIN 3+.

When stratified by age to limit the analysis to women aged 30 and older, the cumulative incidence of CIN 3+ was 20% in HPV-16-positive women and 15% in HPV-18-positive women (FIGURE 1). Contrast these results to the 10-year predictive value of 11% for an LSIL Pap for the same level of cervical neoplasia. In other words, a single positive HPV 16 or 18 test is almost twice as likely to identify women at high risk for CIN 3+ as an LSIL Pap result, over time.

FIGURE 1 Positive HPV 16 or 18 linked to 14% to 17% incidence of CIN3+

The cumulative incidence of CIN 3+ over a 10-year period, as a function of a single HPV test result at enrollment. Women positive for HPV 16 or 18 had a much greater incidence of CIN 3+, compared to women negative for HPV 16 and 18 but positive for other high-risk HPV types by Hybrid Capture 2, or negative for all high-risk HPV types. Adapted from Khan et al.

Follow-up according to risk

These findings support a follow-up strategy that would permit risk stratification of HPV-infected women for whom an optimal repeat screening interval has been unclear.

• Women positive for HPV 16 or 18 warrant referral to colposcopy, for they carry the majority of risk from a positive high-risk HPV test.
• Women positive only for other high-risk types could be reassured of the safety of a 12-month interval without colposcopy, and referred to colposcopy only if the repeat Pap shows worse than atypical squamous cells of undetermined significance (ASC-US) or the HPV test is again positive (FIGURE 2).

FIGURE 2 Type-specific testing in clinical practice

Proposed management of women aged 30 or older, who are screened concurrently with both a Pap test and an HPV test, with typing for HPV 16/18. Adapted from Khan et al.

2 type-specific tests in the pipeline

Currently, the only FDA-approved test for combined screening of women aged 30 and older is the Hybrid Capture 2 High-risk HPV test, which tests for a panel of the 13 most common HPV types known to cause cervical cancer, but does not report on individual types.

But 2 type-specific HPV tests may become available in 2006, which would enable clinicians to follow this strategy.

Digene is nearly ready to launch a 16, 18, 45 type-specific “reflex” test (to a positive Hybrid Capture 2 HPV panel), and Roche is preparing to get its type-specific Linear Array HPV test approved.

2 Better management of screen positives

New practice bulletin on managing abnormal tests

ACOG Practice Bulletin, Number 66. Management of abnormal cervical cytology and histology. Washington, DC: American College of Obstetricians and Gynecologists; September 2005.

The new Practice Bulletin published last September in most respects mirrors the most recent American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus guidelines.¹

Key points

• ASC-US may be managed by referral to immediate colposcopy, by repeat Pap, or by HPV testing. However, “reflex HPV testing” when ASC-US is derived from liquid-based cytology has advantages. (It is estimated that a large majority of ASC-US is now managed by HPV testing.)
• Initial management of all other Pap abnormalities is by immediate referral to colposcopy, ie, the finding of atypical squamous cells cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), LSIL, and high-grade intraepithelial lesions (HSIL).
• Management of ASC-US and LSIL in adolescence and postmenopause: ACOG provides an alternative strategy for adolescents with either ASC-US or LSIL cytology, who may have either repeat cytology at 6 and 12 months or a single HPV test at 12 months. ACOG did not differentiate postmenopausal women with either ASC-US or LSIL as “special situations” with additional management strategies.
• CIN 2/3 should usually be treated, both guidelines say. The only exception is the adolescent with CIN 2, who may be followed with repeat cytology and colposcopy at 4 to 6 months if she is deemed reliable for follow-up, the colposcopy is adequate, and the endocervical sampling is negative.
• HPV-positive ASC-US, ASC-H, or LSIL and either CIN 1 or normal colposcopy findings should be followed by repeat Pap at 6 and 12 months, or a single HPV test at 12 months, with referral to colposcopy if either the Pap results show ASC-US or more advanced abnormality or the HPV test is positive.
• In contrast, an excisional procedure is required for normal findings, or an unsatisfactory colposcopy in nonpregnant women referred for atypical glandular cells “favor neoplasia” (AGC-H), or adenocarcinoma in situ (AIS), or repeat atypical glandular cells “not otherwise specified” (AGC-NOS), or HSIL. The only exception is an adolescent with HSIL cytology and a satisfactory and normal colposcopy and biopsy, who may be followed closely.
• Women treated for CIN 2/3 can be monitored after treatment by cytology screening at 6-month intervals 3 or 4 times or by a single HPV test at 6 months, before returning to annual screening. Any repeat abnormal Pap at the threshold of ASC-US or more advanced abnormality or a positive HPV test requires colposcopic evaluation.

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. American Society for Colposcopy and Cervical Pathology. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

3 HPV vaccine, soon to be in our offices

Vaccines will stop CIN 2/3 and cancer

Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107:18–27.

The HPV 16 vaccine provided 100% protection against development of HPV-16-related CIN 2/3 during an average of 3.5 years of follow-up.

This preliminary study to the Quadrivalent HPV 6, 11, 16, 18 trial on an HPV 16 virus-like particle (VLP) vaccine reached an average of 3.5 years of follow-up. CIN 2/3 developed in 12 of the 750 women receiving placebo, in contrast to none of the 755 vaccine recipients. Persistent HPV 16 infections were defined as testing positive for type-specific HPV 16 on 2 or more visits, with the caveat that women testing positive on the last visit were considered persistent because they would have no further follow-up to determine that status. As a result, some women with a positive test only on the last visit were included as “persisters,” perhaps explaining why the efficacy in preventing persistent HPV 16 in the vaccine recipients was only 94%. Single-test positives can be transient infections, vaginal contamination with infected cells from a partner during recent intercourse, or early persistent infections. Although antibody titers to HPV 16 in vaccine recipients waned over time, they still exceeded titers in placebo recipients who already had natural immunity to HPV 16.

Benefit of the HPV 16 vaccine was also seen for women already HPV-16 positive at enrollment, but only if they were seronegative for HPV 16. It is possible that, if an immune response has not yet been mounted, the vaccine may still have a positive effect for women already HPV-16 infected.

Who will be vaccinated?

Although the primary target group for the HPV vaccine will be children before natural exposure can occur after the onset of sexual activity, many women already sexually active will likely want to be vaccinated.

It is this “catch-up” group that will challenge the OBGyn to become familiar with and to provide the HPV vaccine when it becomes available, likely later this year.

Quadrivalent vaccine 100% effective

Skjeldstad FE, Koutsky LA, for the Merck Phase 3 HPV Vaccine Steering Committee (Future II). Phase II trial of prophylactic quadrivalent HPV 6, 11, 16, 18 L1 virus-like particle (VLP) vaccine; prevention of cervical intraepithelial neoplasia (CIN) 2/3 including adeno- and squamous cell carcinoma in situ (CIS). Presented at: Infectious Diseases Society of America, Late Breaker Session 66, LB–8A; October 7, 2005; San Francisco, Calif.

The Quadrivalent HPV 6, 11, 16, 18 vaccine provided 100% protection against persistent HPV 16/18 and HPV 16/18-related CIN 2/3.

This trial became center stage in the world media in early October 2005, with headlines such as “First anti-cancer vaccine 100% effective.” The results are truly astounding, as there were no CIN 2/3 cases in the Per Protocol group, among the 5,301 women vaccinated, in contrast to 21 cases in the 5,258 women who received the placebo (TABLE 1).

In the group most likely to mirror a typical vaccinated population, only 1 case of HPV-16/18-positive CIN 2/3 occurred in the 5,736 vaccinated women, some of whom were already positive for 1 or more HPV types, or had serologic evidence of prior type-specific infection, or received fewer than the 3 recommended doses. In contrast, 36 HPV-16/18 CIN 2/3 occurred in the 5,766 women who received placebo.

TABLE 1

Efficacy of quadrivalent HPV 6, 11, 16, 18 vaccine in preventing CIN 2/3

No warts, either

Subsequent analysis revealed similar protection from HPV 6 or 11 genital warts.

No serious adverse events were recorded in the entire trial.

Because HPV 16 and 18 together cause approximately 70% of all cervical cancers, and HPV 6 and 11 cause 90% of genital warts, these results are surely something about which to rejoice!

Gardasil and Cervarix vaccines

Now the challenge will be in getting the population vaccinated. Merck is expected to have its Gardasil Quadrivalent vaccine on the market mid- to late 2006. GlaxoSmithKline expects to put Cervarix Bivalent HPV 16, 18 vaccine on the market sometime in 2007.

How HPV vaccine will—and won’t—change practice

Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine. 2005;23:2388–2394.

Cervical screening will continue, but will be more accurate and more efficient.

Yes, we are on the verge of the possibility of reducing the risk of cervical cancer to close to zero, but it will take decades. Vaccinating young girls will not significantly reduce cervical cancer rates until these girls reach the median ages of microinvasive (early 40s) and invasive (late 40s) cervical cancer.

Even then, cervical cancer rates will depend on these factors:

• the extent of vaccination coverage
• the number of high-risk HPV types in the vaccine
• whether vaccination provides multidecade protection or falls off with time
• whether the medical community and the public continue to diligently follow recommended screening guidelines

If immune protection falls with time, booster HPV vaccine shots should provide ongoing protection, but population protection will depend on the percent of the population obtaining the booster. If the population becomes complacent about cervical screening as risk for cervical cancer decreases, then cancers will develop that would have otherwise been prevented.

Why screening will continue

Virus-like particle (VLP) vaccines for all of the important oncogenic HPV types could, theoretically, be produced. But until long after multivalent HPV vaccines that include all the important oncogenic types are available, women will require screening to prevent the 30% of cancers that occur from other high-risk HPV types not in the present vaccine. And, we will need screening to protect women who are not vaccinated, and those already infected.

As Franco and Harper stressed, “Although the future seems bright on the vaccine front, policy makers are strongly cautioned to avoid scaling back cervical cancer screening. Any premature relaxation of cervical cancer control measures already in place will bring a resurgence of the disease to the unacceptable levels of the not too distant past.”

In other words, cervical screening will continue for the foreseeable future.

A peek at a “new world”

Fewer abnormal Pap tests. The vaccine will likely steadily decrease the rate of abnormal Paps that are important, as an increasing proportion of women are vaccinated against the 2 most common types in high-grade CIN.

Colposcopies and cervical treatments will decline in number coincident with the proportion of the population vaccinated.

A training challenge? This change will decrease the number of significant lesions that a colposcopist may see, increasing the challenge of training and maintaining expertise in identification and treatment of these lesions. As significant Pap abnormalities decrease, maintaining expertise in cytologic interpretation, and even in maintaining attention to detail, may become more difficult.

Specific testing. Finding women with significant abnormalities may more and more be accomplished with the accuracy afforded by testing for specific HPV types known to be most at-risk for CIN 3+.

With respect to cervical cancer prevention, the years to come will surely be a new world, different from what we all have known.

It could be the end of the affair with HPV!¹ With this exclamation, Prof. Margaret Stanley, the noted human papillomavirus immunologist, expressed the optimism we all share, now that the possibility of conquering cervical cancer is within view. Not yet 25 years have passed since the first sequencing of a genital HPV type, and scarcely 10 years since the International Agency for Research on Cancer proclaimed that HPV causes cervical cancer. It has been 57 years since the discovery that launched an international quest to reduce the cervical cancer rate: George Papanicolaou’s test for early abnormal cell changes that, decades later, were found to be secondary to HPV. We’ve made great progress. What was the 2nd leading cancer in US women in incidence and mortality is now 11th in incidence and 13th in mortality.

But even with perfect attendance at annual screenings, women still get cervical cancer. And many still do not have screenings—they account for about half of all cervical cancers. And the Pap, as good as it is, has flaws. The test is subjective, and sensitivity varies from lab to lab and country to country.

What is new in 2006 that we may soon be able to put into practice, bringing us closer to a new world—with respect to cervical cancer prevention—different from any we’ve known?

• 1 More sensitive and objective screening
• 2 Better management of screen positives
• 3 HPV vaccine, soon to be in our offices

1 More sensitive and more objective screening

A comforting combo: Negative Pap and HPV tests

ACOG Practice Bulletin, Number 61. Human papillomavirus. Washington, DC: American College of Obstetricians and Gynecologists; April 2005.

Because HPV testing is more sensitive than cervical cytology in detecting CIN 2 and CIN 3, women with concurrent negative Pap and HPV tests can be reassured that their risk of unidentified CIN 2, CIN 3, or cervical cancer is approximately 1 in 1,000. (Level A evidence)

The American Cancer Society and the American College of Obstetricians and Gynecologists have both provided as an option the screening of women age 30 and older with the combination of the Pap and a test for high-risk HPV types.^2,3 These “sophisticated new tests for the detection of HPV…hold great promise for improved screening for cervical cancer precursors and invasive cancer, and for triage of cervical cytology,” the Bulletin states.

Not all women get annual screening, however, and even if they do, the IARC estimates, the lifetime risk for cervical cancer for women who have conventional Paps annually is approximately 216 per 100,000, if the Pap sensitivity is about 70%. The prospect of reducing the risk of missing significant cervical neoplasia at each screen to 1 per 1,000 should be of comfort to women and the clinicians who watch over their health.

Dilemma: Women over 30, with normal Pap and high-risk HPV

What about the approximately 4% of women aged 30 and older with normal cytology and high-risk HPV? How should these women be managed? A panel of experts on HPV and cervical screening published “interim guidance” in 2004, recommending that until further data are available, these women should be retested in 6 to 12 months for persistence of HPV or development of abnormal cytology, and referred to colposcopy if still HPV-positive or if Pap results show low-grade squamous intraepithelial lesion (LSIL) or worse, regardless of HPV result.⁴

Although the April 2005 ACOG Bulletin affirmed that guideline, concern persisted that, while some women so identified might be better evaluated immediately by colposcopy, the majority would not, and there was no good way to identify HPV-positive women most at risk. Several longitudinal studies (discussed in the following section) have now made the path clearer.

REFERENCES

1. Stanley M. The end for genital human papillomavirus infections? Lancet Oncol 2005;6:256-257.

2. Sasow D, Runowicz CD, Solomon D, et al, for the American Cancer Society. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin. 2002;52:342-362.

3. ACOG Practice Bulletin, Number 45. Cervical cytology screening. Washington, DC: American College of Obstetricians and Gynecologists; 2003.

4. 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;103:304-309.

Type-specific testing identifies highest risk

Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–1079.

HPV screening that distinguishes types 16 and 18 from other oncogenic (high-risk) HPV types identifies women at the greatest risk of CIN 2/3+ and may permit less aggressive management of women with other high-risk HPV infections.

The solution to the dilemma of having to wait 6 to 12 months to repeat Pap and HPV tests for women with a normal cytology but a positive HPV test before determining the need for colposcopy may be solved by type-specific HPV testing. The 10-year cumulative incidence of CIN 3 and cervical cancer (CIN 3+) in 20,810 women tested once for HPV at enrollment was only 0.8% in the women who tested negative for high-risk HPV by Hybrid Capture 2. In contrast, CIN 3+ developed in 17% of the HPV-16-positive women and 14% of the HPV-18-positive women within 10 years.

Women positive for other high-risk types of HPV, but negative for HPV 16 and 18 had far less risk: only 3% developed CIN 3+.

When stratified by age to limit the analysis to women aged 30 and older, the cumulative incidence of CIN 3+ was 20% in HPV-16-positive women and 15% in HPV-18-positive women (FIGURE 1). Contrast these results to the 10-year predictive value of 11% for an LSIL Pap for the same level of cervical neoplasia. In other words, a single positive HPV 16 or 18 test is almost twice as likely to identify women at high risk for CIN 3+ as an LSIL Pap result, over time.

FIGURE 1 Positive HPV 16 or 18 linked to 14% to 17% incidence of CIN3+

The cumulative incidence of CIN 3+ over a 10-year period, as a function of a single HPV test result at enrollment. Women positive for HPV 16 or 18 had a much greater incidence of CIN 3+, compared to women negative for HPV 16 and 18 but positive for other high-risk HPV types by Hybrid Capture 2, or negative for all high-risk HPV types. Adapted from Khan et al.

Follow-up according to risk

These findings support a follow-up strategy that would permit risk stratification of HPV-infected women for whom an optimal repeat screening interval has been unclear.

• Women positive for HPV 16 or 18 warrant referral to colposcopy, for they carry the majority of risk from a positive high-risk HPV test.
• Women positive only for other high-risk types could be reassured of the safety of a 12-month interval without colposcopy, and referred to colposcopy only if the repeat Pap shows worse than atypical squamous cells of undetermined significance (ASC-US) or the HPV test is again positive (FIGURE 2).

FIGURE 2 Type-specific testing in clinical practice

Proposed management of women aged 30 or older, who are screened concurrently with both a Pap test and an HPV test, with typing for HPV 16/18. Adapted from Khan et al.

2 type-specific tests in the pipeline

Currently, the only FDA-approved test for combined screening of women aged 30 and older is the Hybrid Capture 2 High-risk HPV test, which tests for a panel of the 13 most common HPV types known to cause cervical cancer, but does not report on individual types.

But 2 type-specific HPV tests may become available in 2006, which would enable clinicians to follow this strategy.

Digene is nearly ready to launch a 16, 18, 45 type-specific “reflex” test (to a positive Hybrid Capture 2 HPV panel), and Roche is preparing to get its type-specific Linear Array HPV test approved.

2 Better management of screen positives

New practice bulletin on managing abnormal tests

ACOG Practice Bulletin, Number 66. Management of abnormal cervical cytology and histology. Washington, DC: American College of Obstetricians and Gynecologists; September 2005.

The new Practice Bulletin published last September in most respects mirrors the most recent American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus guidelines.¹

Key points

• ASC-US may be managed by referral to immediate colposcopy, by repeat Pap, or by HPV testing. However, “reflex HPV testing” when ASC-US is derived from liquid-based cytology has advantages. (It is estimated that a large majority of ASC-US is now managed by HPV testing.)
• Initial management of all other Pap abnormalities is by immediate referral to colposcopy, ie, the finding of atypical squamous cells cannot rule out high-grade (ASC-H), atypical glandular cells (AGC), LSIL, and high-grade intraepithelial lesions (HSIL).
• Management of ASC-US and LSIL in adolescence and postmenopause: ACOG provides an alternative strategy for adolescents with either ASC-US or LSIL cytology, who may have either repeat cytology at 6 and 12 months or a single HPV test at 12 months. ACOG did not differentiate postmenopausal women with either ASC-US or LSIL as “special situations” with additional management strategies.
• CIN 2/3 should usually be treated, both guidelines say. The only exception is the adolescent with CIN 2, who may be followed with repeat cytology and colposcopy at 4 to 6 months if she is deemed reliable for follow-up, the colposcopy is adequate, and the endocervical sampling is negative.
• HPV-positive ASC-US, ASC-H, or LSIL and either CIN 1 or normal colposcopy findings should be followed by repeat Pap at 6 and 12 months, or a single HPV test at 12 months, with referral to colposcopy if either the Pap results show ASC-US or more advanced abnormality or the HPV test is positive.
• In contrast, an excisional procedure is required for normal findings, or an unsatisfactory colposcopy in nonpregnant women referred for atypical glandular cells “favor neoplasia” (AGC-H), or adenocarcinoma in situ (AIS), or repeat atypical glandular cells “not otherwise specified” (AGC-NOS), or HSIL. The only exception is an adolescent with HSIL cytology and a satisfactory and normal colposcopy and biopsy, who may be followed closely.
• Women treated for CIN 2/3 can be monitored after treatment by cytology screening at 6-month intervals 3 or 4 times or by a single HPV test at 6 months, before returning to annual screening. Any repeat abnormal Pap at the threshold of ASC-US or more advanced abnormality or a positive HPV test requires colposcopic evaluation.

REFERENCES

1. Wright TC, Jr, Cox JT, Massad LS, Carlson J, Twiggs LB, Wilkinson EJ. American Society for Colposcopy and Cervical Pathology. 2001 consensus guidelines for the management of women with cervical intraepithelial neoplasia. Am J Obstet Gynecol. 2003;189:295-304.

3 HPV vaccine, soon to be in our offices

Vaccines will stop CIN 2/3 and cancer

Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107:18–27.

The HPV 16 vaccine provided 100% protection against development of HPV-16-related CIN 2/3 during an average of 3.5 years of follow-up.

This preliminary study to the Quadrivalent HPV 6, 11, 16, 18 trial on an HPV 16 virus-like particle (VLP) vaccine reached an average of 3.5 years of follow-up. CIN 2/3 developed in 12 of the 750 women receiving placebo, in contrast to none of the 755 vaccine recipients. Persistent HPV 16 infections were defined as testing positive for type-specific HPV 16 on 2 or more visits, with the caveat that women testing positive on the last visit were considered persistent because they would have no further follow-up to determine that status. As a result, some women with a positive test only on the last visit were included as “persisters,” perhaps explaining why the efficacy in preventing persistent HPV 16 in the vaccine recipients was only 94%. Single-test positives can be transient infections, vaginal contamination with infected cells from a partner during recent intercourse, or early persistent infections. Although antibody titers to HPV 16 in vaccine recipients waned over time, they still exceeded titers in placebo recipients who already had natural immunity to HPV 16.

Benefit of the HPV 16 vaccine was also seen for women already HPV-16 positive at enrollment, but only if they were seronegative for HPV 16. It is possible that, if an immune response has not yet been mounted, the vaccine may still have a positive effect for women already HPV-16 infected.

Who will be vaccinated?

Although the primary target group for the HPV vaccine will be children before natural exposure can occur after the onset of sexual activity, many women already sexually active will likely want to be vaccinated.

It is this “catch-up” group that will challenge the OBGyn to become familiar with and to provide the HPV vaccine when it becomes available, likely later this year.

Quadrivalent vaccine 100% effective

Skjeldstad FE, Koutsky LA, for the Merck Phase 3 HPV Vaccine Steering Committee (Future II). Phase II trial of prophylactic quadrivalent HPV 6, 11, 16, 18 L1 virus-like particle (VLP) vaccine; prevention of cervical intraepithelial neoplasia (CIN) 2/3 including adeno- and squamous cell carcinoma in situ (CIS). Presented at: Infectious Diseases Society of America, Late Breaker Session 66, LB–8A; October 7, 2005; San Francisco, Calif.

The Quadrivalent HPV 6, 11, 16, 18 vaccine provided 100% protection against persistent HPV 16/18 and HPV 16/18-related CIN 2/3.

This trial became center stage in the world media in early October 2005, with headlines such as “First anti-cancer vaccine 100% effective.” The results are truly astounding, as there were no CIN 2/3 cases in the Per Protocol group, among the 5,301 women vaccinated, in contrast to 21 cases in the 5,258 women who received the placebo (TABLE 1).

In the group most likely to mirror a typical vaccinated population, only 1 case of HPV-16/18-positive CIN 2/3 occurred in the 5,736 vaccinated women, some of whom were already positive for 1 or more HPV types, or had serologic evidence of prior type-specific infection, or received fewer than the 3 recommended doses. In contrast, 36 HPV-16/18 CIN 2/3 occurred in the 5,766 women who received placebo.

TABLE 1

Efficacy of quadrivalent HPV 6, 11, 16, 18 vaccine in preventing CIN 2/3

No warts, either

Subsequent analysis revealed similar protection from HPV 6 or 11 genital warts.

No serious adverse events were recorded in the entire trial.

Because HPV 16 and 18 together cause approximately 70% of all cervical cancers, and HPV 6 and 11 cause 90% of genital warts, these results are surely something about which to rejoice!

Gardasil and Cervarix vaccines

Now the challenge will be in getting the population vaccinated. Merck is expected to have its Gardasil Quadrivalent vaccine on the market mid- to late 2006. GlaxoSmithKline expects to put Cervarix Bivalent HPV 16, 18 vaccine on the market sometime in 2007.

How HPV vaccine will—and won’t—change practice

Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine. 2005;23:2388–2394.

Cervical screening will continue, but will be more accurate and more efficient.

Yes, we are on the verge of the possibility of reducing the risk of cervical cancer to close to zero, but it will take decades. Vaccinating young girls will not significantly reduce cervical cancer rates until these girls reach the median ages of microinvasive (early 40s) and invasive (late 40s) cervical cancer.

Even then, cervical cancer rates will depend on these factors:

• the extent of vaccination coverage
• the number of high-risk HPV types in the vaccine
• whether vaccination provides multidecade protection or falls off with time
• whether the medical community and the public continue to diligently follow recommended screening guidelines

If immune protection falls with time, booster HPV vaccine shots should provide ongoing protection, but population protection will depend on the percent of the population obtaining the booster. If the population becomes complacent about cervical screening as risk for cervical cancer decreases, then cancers will develop that would have otherwise been prevented.

Why screening will continue

Virus-like particle (VLP) vaccines for all of the important oncogenic HPV types could, theoretically, be produced. But until long after multivalent HPV vaccines that include all the important oncogenic types are available, women will require screening to prevent the 30% of cancers that occur from other high-risk HPV types not in the present vaccine. And, we will need screening to protect women who are not vaccinated, and those already infected.

As Franco and Harper stressed, “Although the future seems bright on the vaccine front, policy makers are strongly cautioned to avoid scaling back cervical cancer screening. Any premature relaxation of cervical cancer control measures already in place will bring a resurgence of the disease to the unacceptable levels of the not too distant past.”

In other words, cervical screening will continue for the foreseeable future.

A peek at a “new world”

Fewer abnormal Pap tests. The vaccine will likely steadily decrease the rate of abnormal Paps that are important, as an increasing proportion of women are vaccinated against the 2 most common types in high-grade CIN.

Colposcopies and cervical treatments will decline in number coincident with the proportion of the population vaccinated.

A training challenge? This change will decrease the number of significant lesions that a colposcopist may see, increasing the challenge of training and maintaining expertise in identification and treatment of these lesions. As significant Pap abnormalities decrease, maintaining expertise in cytologic interpretation, and even in maintaining attention to detail, may become more difficult.

Specific testing. Finding women with significant abnormalities may more and more be accomplished with the accuracy afforded by testing for specific HPV types known to be most at-risk for CIN 3+.

With respect to cervical cancer prevention, the years to come will surely be a new world, different from what we all have known.