Thomas C. Wright Jr, MD

Transmission of HPV

Most papillomavirus infections are transmitted through close skin-to-skin or mucosa-to-mucosa contact. Epidemiologic studies clearly indicate that sexual intercourse is the primary route for anogenital HPV infection.¹ Infection is relatively uncommon in women who have not had intercourse, and there is a strong and consistent relationship between the number of both lifetime and recent sexual partners and the prevalence of HPV in women. There is also a strong association between having had a recent new sexual partner(s) and incident anogenital HPV infection. Consistent condom use reduces—but does not eliminate—HPV transmission.² In a prospective study on college students who initiated sexual intercourse either after or immediately prior to enrollment, the overall rate of anogenital HPV infection was 89 per 100 patient-years of follow-up in those whose partners rarely used condoms during sexual intercourse, compared with 38 per 100 patient-years of follow-up among those whose partners always used condoms.

Penetrative sexual intercourse is not a requirement for HPV transmission. Both oral and digital HPV infections occur, and there is evidence that digital-genital and oral-genital contact can result in the transmission of HPV, albeit at relatively low rates. In a study of college students from Seattle, the 2-year cumulative incidence of HPV infections was 38.8% in those who were sexually active at enrollment.³ Among college students who remained virginal, the 2-year cumulative incidence of HPV was 9.7% in those who reported nonpenetrative sexual contact, but only 1.3% in those who reported no sexual contact whatsoever. HPV also can be transmitted perinatally.¹

Although the clinical significance of HPV perinatal transmission is unknown, this route of transmission is well documented. A recent study of oral and genital HPV infections in infants born to both HPV-positive and HPV-negative women detected HPV DNA in 6% of the infants at birth, 13% at 6 weeks after birth, and 9% between 3 to 24 months of age.⁴ Approximately half of the HPV infections in infants were oral and half were genital. Interestingly, persistence of HPV infection was uncommon in the newborns—only 1.4% had the same HPV type detected on 2 or more occasions. Therefore, most of these infections appear to be very transient, and it is unlikely that the majority have adverse clinical consequences.

Initial HPV infections and prevalence of HPV in the population

Most sexually active adolescents and women become infected with HPV within several years of initiating sexual activity. A prospective follow-up study of sexually naïve college students found that within 12 months of initiating sexual intercourse, 30% became HPV positive; within 48 months, 54% were HPV positive.³ Other follow-up studies of adolescents and young women have found that with repeated testing and long-term follow-up, HPV is detected in more than two-thirds over a several-year period.^5-7

Women with transient HPV infections often develop cytological abnormalities while they are actively shedding HPV DNA. This occurs because productive HPV infections result in cytological abnormalities in the infected epithelial cells. Cells with these cytological features are found in about one-third of HPV-infected women and result in a diagnosis of either low-grade squamous intraepithelial lesions (LSIL) or atypical squamous cells of undetermined significance (ASC-US).⁸ If followed, cytological abnormalities continue to be detected for approximately 1 to 2 years, but by 4 years, the risk of having an abnormal cervical cytology is similar to that of women in the general population.⁹

The majority of HPV infections are self-limited and spontaneously clear within a several-year period as a result of cell-mediated immunity. In one study, two-thirds of adolescents infected with low-risk HPV types spontaneously cleared their infections by 12 months, as did over half of those infected with high-risk HPV types ( FIGURE 1 ).⁵ By 23 months, more than 80% had cleared their HPV infections. In another follow-up study of adolescents and young women with LSIL, 91% of HPV-infected individuals cleared their infections after 36 months of follow-up.¹⁰ However, many women who spontaneously clear one specific type of HPV become infected with another HPV type. This is part of the reason that infection with multiple types of HPV is quite common in sexually active adolescents and young women.

The natural history of HPV infections explains the prevalence of HPV infection in women in the general population. Since infection is sexually transmitted and is usually transient, the prevalence of HPV infections is highest among sexually active women in their 20s. With increasing age, women tend to have fewer new sexual partners, and prevalence decreases. After age 45, the prevalence of high-risk HPV infections tends to stabilize, and less than 5% of women in the general population are DNA positive for high-risk types of HPV. The prevalence of HPV DNA positivity drops to less than 3% of women with a normal cervical cytology result.¹¹

 

It is unclear how many HPV-infected women who become HPV DNA negative actually have complete viral clearance and how many continue to harbor the viral genome in the basal cells of the squamous epithelium, but at such a low copy number that they cannot be detected using standard molecular tests. Such undetectable, low-level infections are usually referred to as “latent infections” and are similar to the latent infections that are seen with herpes simplex virus and varicella zoster. The finding that almost all HIV-infected individuals become HPV DNA positive as they become more profoundly immunosuppressed suggests that HPV viral latency clearly occurs.¹²

Reactivation of a latent infection secondary to senescence of HPV-directed cellular immunity could easily explain many of the HPV infections that are detected in older women with a previously normal screening history and no new sexual partners.⁸ Currently, it is impossible to distinguish between reactivation of a latent HPV infection and a newly acquired infection. It should also be noted that the risk for subsequently developing either cervical intraepithelial neoplasia (CIN) 2,3 or cervical cancer after reactivation of a latent infection appears to be relatively low in women who have a history of 3 or more normal cervical cytology results.¹³ This conclusion is based on the fact that although 4% to 5% of women 45 years and older are at high risk for becoming HPV DNA positive at any single point in time, the risk that these women will have CIN 2,3 or cervical cancer detected during routine screening is minimal (≤0.05%).¹³

FIGURE 1
Clearance of HPV infections

HPV, human papillomavirus.
Kaplan-Meier estimates of clearance time of high-risk (HR) and low risk (LR) HPV infection. The median clearance time for high-risk HPV was 226 days.
Reprinted with permission from Brown DR, et al. J Infect Dis. 2005:191:182-192. Copyright 2004 by the Infectious Diseases Society of America, University of Chicago Press. All rights reserved.

Persistent HPV infections and the development of CIN 2,3

Only about 10% of HPV infections persist for more than 3 years. The longer a specific HPV infection persists, the lower the probability that the lesion will clear spontaneously and the higher the probability that a CIN 2,3 lesion or cervical cancer will develop.⁸ Prevalent HPV infections detected at the time of cervical cancer screening tend to persist longer in older women compared to younger women. This may be due to the fact that the infections identified in older women are more likely to represent infections that have already been persistent for several years, whereas infections in younger women are more likely to represent recently acquired infections. There is no established definition of what constitutes clinically important persistence, but most management recommendations consider persistence for 12 months to be clinically significant and therefore warrant colposcopy.

Since high-risk HPV DNA is detected in almost all CIN 2,3 lesions and invasive cervical cancers, it is clear that persistence of infection with a high-risk HPV is a requirement for the development of these lesions. New data demonstrate that the time required for an initial HPV infection to progress to a CIN 2,3 lesion can be quite short. In college-aged women, incident infection associated with any HPV type results in an 11% cumulative incidence of biopsy-confirmed CIN 2,3 by 36 months.¹⁴ For incident HPV 16 or HPV 18 infections, the cumulative incidence of CIN 2,3 at 36 months is 27% (FIGURE 2). Similarly, Mao et al followed young women in the placebo arm of an HPV 16 vaccine trial and found that all but one case of CIN 2,3 occurring after an incident HPV 16 infection developed within 12 months (FIGURE 2).¹⁵ It should be emphasized, however, that it takes almost a decade for a CIN 2,3 lesion to progress to invasive cervical cancer; therefore, it is safe to extend the screening interval to 3 years or more in women who are found to be both high-risk HPV DNA and cytology negative during routine screening.

We also have a much better understanding of the risk of being diagnosed with CIN 2,3 or cervical cancer in older, high-risk HPV DNA-positive women. In a records linkage study of Danish women who were initially cytologically negative after 3 years, CIN 2,3 or cervical cancer had been diagnosed in 6.3% of high-risk HPV-positive women.¹⁶ The cumulative detection of CIN 2,3 was 11.3% and 22.9% after 5 and 10 years of follow-up, respectively. In comparison, CIN 2,3 was diagnosed after 10 years of follow-up in only 1.9% of the HPV-negative women. A Swedish study that included all women, irrespective of cytology results, detected CIN 2,3 in 37% of women who were HPV 16 positive and 26% of those who were HPV 18 positive after 4 years of follow-up ( TABLE ).¹⁷ Importantly, in this Swedish study, CIN 2,3 lesions were detected in a substantial number of women infected with other high-risk types of HPV, including HPV 31, 33, 52, and 58. This finding contrasts with the results from a study by the National Cancer Institutes (NCI), at Kaiser, Portland, Oregon.¹⁸ In a Kaiser follow-up study of 20,810 women, the cumulative detection of CIN 3 after 10 years of follow-up was 20.7% in HPV 16-positive women >30 years of age with negative cytology; 17.7% for those with HPV 18; 1.5% for those with other high-risk types of HPV; and 0.5% for HPV DNA-negative women.

 

FIGURE 2
Cumulative detection of CIN 2,3 after incident HPV infections in two studies

HPV, human papillomavirus.
After incident HPV 16 infection (green line) and after incident HPV 16 or 18 infection (blue line).
Modified from Winer RL, et al. J Infect Dis. 2005;191:731-738 (blue line); Mao C, et al. Obstet Gynecol. 2006;107:18-27 (green line).

TABLE
Detection of CIN 2,3 or cancer

HPV status	Percent with CIN 2+*
HPV negative	0.4%
HPV 16	37%
HPV 18	26%
HPV 31	37%
HPV 33	48%
HPV 52	26%
HPV 58	30%
CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.
*Percentage of women diagnosed with CIN 2,3 or cancer during a 4-year follow-up period.
Modified from Naucler P, et al. Br J Cancer. 2007;97:129-132.

Transmission of HPV

Most papillomavirus infections are transmitted through close skin-to-skin or mucosa-to-mucosa contact. Epidemiologic studies clearly indicate that sexual intercourse is the primary route for anogenital HPV infection.¹ Infection is relatively uncommon in women who have not had intercourse, and there is a strong and consistent relationship between the number of both lifetime and recent sexual partners and the prevalence of HPV in women. There is also a strong association between having had a recent new sexual partner(s) and incident anogenital HPV infection. Consistent condom use reduces—but does not eliminate—HPV transmission.² In a prospective study on college students who initiated sexual intercourse either after or immediately prior to enrollment, the overall rate of anogenital HPV infection was 89 per 100 patient-years of follow-up in those whose partners rarely used condoms during sexual intercourse, compared with 38 per 100 patient-years of follow-up among those whose partners always used condoms.

Penetrative sexual intercourse is not a requirement for HPV transmission. Both oral and digital HPV infections occur, and there is evidence that digital-genital and oral-genital contact can result in the transmission of HPV, albeit at relatively low rates. In a study of college students from Seattle, the 2-year cumulative incidence of HPV infections was 38.8% in those who were sexually active at enrollment.³ Among college students who remained virginal, the 2-year cumulative incidence of HPV was 9.7% in those who reported nonpenetrative sexual contact, but only 1.3% in those who reported no sexual contact whatsoever. HPV also can be transmitted perinatally.¹

Although the clinical significance of HPV perinatal transmission is unknown, this route of transmission is well documented. A recent study of oral and genital HPV infections in infants born to both HPV-positive and HPV-negative women detected HPV DNA in 6% of the infants at birth, 13% at 6 weeks after birth, and 9% between 3 to 24 months of age.⁴ Approximately half of the HPV infections in infants were oral and half were genital. Interestingly, persistence of HPV infection was uncommon in the newborns—only 1.4% had the same HPV type detected on 2 or more occasions. Therefore, most of these infections appear to be very transient, and it is unlikely that the majority have adverse clinical consequences.

Initial HPV infections and prevalence of HPV in the population

Most sexually active adolescents and women become infected with HPV within several years of initiating sexual activity. A prospective follow-up study of sexually naïve college students found that within 12 months of initiating sexual intercourse, 30% became HPV positive; within 48 months, 54% were HPV positive.³ Other follow-up studies of adolescents and young women have found that with repeated testing and long-term follow-up, HPV is detected in more than two-thirds over a several-year period.^5-7

Women with transient HPV infections often develop cytological abnormalities while they are actively shedding HPV DNA. This occurs because productive HPV infections result in cytological abnormalities in the infected epithelial cells. Cells with these cytological features are found in about one-third of HPV-infected women and result in a diagnosis of either low-grade squamous intraepithelial lesions (LSIL) or atypical squamous cells of undetermined significance (ASC-US).⁸ If followed, cytological abnormalities continue to be detected for approximately 1 to 2 years, but by 4 years, the risk of having an abnormal cervical cytology is similar to that of women in the general population.⁹

The majority of HPV infections are self-limited and spontaneously clear within a several-year period as a result of cell-mediated immunity. In one study, two-thirds of adolescents infected with low-risk HPV types spontaneously cleared their infections by 12 months, as did over half of those infected with high-risk HPV types ( FIGURE 1 ).⁵ By 23 months, more than 80% had cleared their HPV infections. In another follow-up study of adolescents and young women with LSIL, 91% of HPV-infected individuals cleared their infections after 36 months of follow-up.¹⁰ However, many women who spontaneously clear one specific type of HPV become infected with another HPV type. This is part of the reason that infection with multiple types of HPV is quite common in sexually active adolescents and young women.

The natural history of HPV infections explains the prevalence of HPV infection in women in the general population. Since infection is sexually transmitted and is usually transient, the prevalence of HPV infections is highest among sexually active women in their 20s. With increasing age, women tend to have fewer new sexual partners, and prevalence decreases. After age 45, the prevalence of high-risk HPV infections tends to stabilize, and less than 5% of women in the general population are DNA positive for high-risk types of HPV. The prevalence of HPV DNA positivity drops to less than 3% of women with a normal cervical cytology result.¹¹

 

It is unclear how many HPV-infected women who become HPV DNA negative actually have complete viral clearance and how many continue to harbor the viral genome in the basal cells of the squamous epithelium, but at such a low copy number that they cannot be detected using standard molecular tests. Such undetectable, low-level infections are usually referred to as “latent infections” and are similar to the latent infections that are seen with herpes simplex virus and varicella zoster. The finding that almost all HIV-infected individuals become HPV DNA positive as they become more profoundly immunosuppressed suggests that HPV viral latency clearly occurs.¹²

Reactivation of a latent infection secondary to senescence of HPV-directed cellular immunity could easily explain many of the HPV infections that are detected in older women with a previously normal screening history and no new sexual partners.⁸ Currently, it is impossible to distinguish between reactivation of a latent HPV infection and a newly acquired infection. It should also be noted that the risk for subsequently developing either cervical intraepithelial neoplasia (CIN) 2,3 or cervical cancer after reactivation of a latent infection appears to be relatively low in women who have a history of 3 or more normal cervical cytology results.¹³ This conclusion is based on the fact that although 4% to 5% of women 45 years and older are at high risk for becoming HPV DNA positive at any single point in time, the risk that these women will have CIN 2,3 or cervical cancer detected during routine screening is minimal (≤0.05%).¹³

FIGURE 1
Clearance of HPV infections

HPV, human papillomavirus.
Kaplan-Meier estimates of clearance time of high-risk (HR) and low risk (LR) HPV infection. The median clearance time for high-risk HPV was 226 days.
Reprinted with permission from Brown DR, et al. J Infect Dis. 2005:191:182-192. Copyright 2004 by the Infectious Diseases Society of America, University of Chicago Press. All rights reserved.

Persistent HPV infections and the development of CIN 2,3

Only about 10% of HPV infections persist for more than 3 years. The longer a specific HPV infection persists, the lower the probability that the lesion will clear spontaneously and the higher the probability that a CIN 2,3 lesion or cervical cancer will develop.⁸ Prevalent HPV infections detected at the time of cervical cancer screening tend to persist longer in older women compared to younger women. This may be due to the fact that the infections identified in older women are more likely to represent infections that have already been persistent for several years, whereas infections in younger women are more likely to represent recently acquired infections. There is no established definition of what constitutes clinically important persistence, but most management recommendations consider persistence for 12 months to be clinically significant and therefore warrant colposcopy.

Since high-risk HPV DNA is detected in almost all CIN 2,3 lesions and invasive cervical cancers, it is clear that persistence of infection with a high-risk HPV is a requirement for the development of these lesions. New data demonstrate that the time required for an initial HPV infection to progress to a CIN 2,3 lesion can be quite short. In college-aged women, incident infection associated with any HPV type results in an 11% cumulative incidence of biopsy-confirmed CIN 2,3 by 36 months.¹⁴ For incident HPV 16 or HPV 18 infections, the cumulative incidence of CIN 2,3 at 36 months is 27% (FIGURE 2). Similarly, Mao et al followed young women in the placebo arm of an HPV 16 vaccine trial and found that all but one case of CIN 2,3 occurring after an incident HPV 16 infection developed within 12 months (FIGURE 2).¹⁵ It should be emphasized, however, that it takes almost a decade for a CIN 2,3 lesion to progress to invasive cervical cancer; therefore, it is safe to extend the screening interval to 3 years or more in women who are found to be both high-risk HPV DNA and cytology negative during routine screening.

We also have a much better understanding of the risk of being diagnosed with CIN 2,3 or cervical cancer in older, high-risk HPV DNA-positive women. In a records linkage study of Danish women who were initially cytologically negative after 3 years, CIN 2,3 or cervical cancer had been diagnosed in 6.3% of high-risk HPV-positive women.¹⁶ The cumulative detection of CIN 2,3 was 11.3% and 22.9% after 5 and 10 years of follow-up, respectively. In comparison, CIN 2,3 was diagnosed after 10 years of follow-up in only 1.9% of the HPV-negative women. A Swedish study that included all women, irrespective of cytology results, detected CIN 2,3 in 37% of women who were HPV 16 positive and 26% of those who were HPV 18 positive after 4 years of follow-up ( TABLE ).¹⁷ Importantly, in this Swedish study, CIN 2,3 lesions were detected in a substantial number of women infected with other high-risk types of HPV, including HPV 31, 33, 52, and 58. This finding contrasts with the results from a study by the National Cancer Institutes (NCI), at Kaiser, Portland, Oregon.¹⁸ In a Kaiser follow-up study of 20,810 women, the cumulative detection of CIN 3 after 10 years of follow-up was 20.7% in HPV 16-positive women >30 years of age with negative cytology; 17.7% for those with HPV 18; 1.5% for those with other high-risk types of HPV; and 0.5% for HPV DNA-negative women.

 

FIGURE 2
Cumulative detection of CIN 2,3 after incident HPV infections in two studies

HPV, human papillomavirus.
After incident HPV 16 infection (green line) and after incident HPV 16 or 18 infection (blue line).
Modified from Winer RL, et al. J Infect Dis. 2005;191:731-738 (blue line); Mao C, et al. Obstet Gynecol. 2006;107:18-27 (green line).

TABLE
Detection of CIN 2,3 or cancer

HPV status	Percent with CIN 2+*
HPV negative	0.4%
HPV 16	37%
HPV 18	26%
HPV 31	37%
HPV 33	48%
HPV 52	26%
HPV 58	30%
CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.
*Percentage of women diagnosed with CIN 2,3 or cancer during a 4-year follow-up period.
Modified from Naucler P, et al. Br J Cancer. 2007;97:129-132.

Transmission of HPV

Most papillomavirus infections are transmitted through close skin-to-skin or mucosa-to-mucosa contact. Epidemiologic studies clearly indicate that sexual intercourse is the primary route for anogenital HPV infection.¹ Infection is relatively uncommon in women who have not had intercourse, and there is a strong and consistent relationship between the number of both lifetime and recent sexual partners and the prevalence of HPV in women. There is also a strong association between having had a recent new sexual partner(s) and incident anogenital HPV infection. Consistent condom use reduces—but does not eliminate—HPV transmission.² In a prospective study on college students who initiated sexual intercourse either after or immediately prior to enrollment, the overall rate of anogenital HPV infection was 89 per 100 patient-years of follow-up in those whose partners rarely used condoms during sexual intercourse, compared with 38 per 100 patient-years of follow-up among those whose partners always used condoms.

Penetrative sexual intercourse is not a requirement for HPV transmission. Both oral and digital HPV infections occur, and there is evidence that digital-genital and oral-genital contact can result in the transmission of HPV, albeit at relatively low rates. In a study of college students from Seattle, the 2-year cumulative incidence of HPV infections was 38.8% in those who were sexually active at enrollment.³ Among college students who remained virginal, the 2-year cumulative incidence of HPV was 9.7% in those who reported nonpenetrative sexual contact, but only 1.3% in those who reported no sexual contact whatsoever. HPV also can be transmitted perinatally.¹

Although the clinical significance of HPV perinatal transmission is unknown, this route of transmission is well documented. A recent study of oral and genital HPV infections in infants born to both HPV-positive and HPV-negative women detected HPV DNA in 6% of the infants at birth, 13% at 6 weeks after birth, and 9% between 3 to 24 months of age.⁴ Approximately half of the HPV infections in infants were oral and half were genital. Interestingly, persistence of HPV infection was uncommon in the newborns—only 1.4% had the same HPV type detected on 2 or more occasions. Therefore, most of these infections appear to be very transient, and it is unlikely that the majority have adverse clinical consequences.

Initial HPV infections and prevalence of HPV in the population

Most sexually active adolescents and women become infected with HPV within several years of initiating sexual activity. A prospective follow-up study of sexually naïve college students found that within 12 months of initiating sexual intercourse, 30% became HPV positive; within 48 months, 54% were HPV positive.³ Other follow-up studies of adolescents and young women have found that with repeated testing and long-term follow-up, HPV is detected in more than two-thirds over a several-year period.^5-7

Women with transient HPV infections often develop cytological abnormalities while they are actively shedding HPV DNA. This occurs because productive HPV infections result in cytological abnormalities in the infected epithelial cells. Cells with these cytological features are found in about one-third of HPV-infected women and result in a diagnosis of either low-grade squamous intraepithelial lesions (LSIL) or atypical squamous cells of undetermined significance (ASC-US).⁸ If followed, cytological abnormalities continue to be detected for approximately 1 to 2 years, but by 4 years, the risk of having an abnormal cervical cytology is similar to that of women in the general population.⁹

The majority of HPV infections are self-limited and spontaneously clear within a several-year period as a result of cell-mediated immunity. In one study, two-thirds of adolescents infected with low-risk HPV types spontaneously cleared their infections by 12 months, as did over half of those infected with high-risk HPV types ( FIGURE 1 ).⁵ By 23 months, more than 80% had cleared their HPV infections. In another follow-up study of adolescents and young women with LSIL, 91% of HPV-infected individuals cleared their infections after 36 months of follow-up.¹⁰ However, many women who spontaneously clear one specific type of HPV become infected with another HPV type. This is part of the reason that infection with multiple types of HPV is quite common in sexually active adolescents and young women.

The natural history of HPV infections explains the prevalence of HPV infection in women in the general population. Since infection is sexually transmitted and is usually transient, the prevalence of HPV infections is highest among sexually active women in their 20s. With increasing age, women tend to have fewer new sexual partners, and prevalence decreases. After age 45, the prevalence of high-risk HPV infections tends to stabilize, and less than 5% of women in the general population are DNA positive for high-risk types of HPV. The prevalence of HPV DNA positivity drops to less than 3% of women with a normal cervical cytology result.¹¹

 

It is unclear how many HPV-infected women who become HPV DNA negative actually have complete viral clearance and how many continue to harbor the viral genome in the basal cells of the squamous epithelium, but at such a low copy number that they cannot be detected using standard molecular tests. Such undetectable, low-level infections are usually referred to as “latent infections” and are similar to the latent infections that are seen with herpes simplex virus and varicella zoster. The finding that almost all HIV-infected individuals become HPV DNA positive as they become more profoundly immunosuppressed suggests that HPV viral latency clearly occurs.¹²

Reactivation of a latent infection secondary to senescence of HPV-directed cellular immunity could easily explain many of the HPV infections that are detected in older women with a previously normal screening history and no new sexual partners.⁸ Currently, it is impossible to distinguish between reactivation of a latent HPV infection and a newly acquired infection. It should also be noted that the risk for subsequently developing either cervical intraepithelial neoplasia (CIN) 2,3 or cervical cancer after reactivation of a latent infection appears to be relatively low in women who have a history of 3 or more normal cervical cytology results.¹³ This conclusion is based on the fact that although 4% to 5% of women 45 years and older are at high risk for becoming HPV DNA positive at any single point in time, the risk that these women will have CIN 2,3 or cervical cancer detected during routine screening is minimal (≤0.05%).¹³

FIGURE 1
Clearance of HPV infections

HPV, human papillomavirus.
Kaplan-Meier estimates of clearance time of high-risk (HR) and low risk (LR) HPV infection. The median clearance time for high-risk HPV was 226 days.
Reprinted with permission from Brown DR, et al. J Infect Dis. 2005:191:182-192. Copyright 2004 by the Infectious Diseases Society of America, University of Chicago Press. All rights reserved.

Persistent HPV infections and the development of CIN 2,3

Only about 10% of HPV infections persist for more than 3 years. The longer a specific HPV infection persists, the lower the probability that the lesion will clear spontaneously and the higher the probability that a CIN 2,3 lesion or cervical cancer will develop.⁸ Prevalent HPV infections detected at the time of cervical cancer screening tend to persist longer in older women compared to younger women. This may be due to the fact that the infections identified in older women are more likely to represent infections that have already been persistent for several years, whereas infections in younger women are more likely to represent recently acquired infections. There is no established definition of what constitutes clinically important persistence, but most management recommendations consider persistence for 12 months to be clinically significant and therefore warrant colposcopy.

Since high-risk HPV DNA is detected in almost all CIN 2,3 lesions and invasive cervical cancers, it is clear that persistence of infection with a high-risk HPV is a requirement for the development of these lesions. New data demonstrate that the time required for an initial HPV infection to progress to a CIN 2,3 lesion can be quite short. In college-aged women, incident infection associated with any HPV type results in an 11% cumulative incidence of biopsy-confirmed CIN 2,3 by 36 months.¹⁴ For incident HPV 16 or HPV 18 infections, the cumulative incidence of CIN 2,3 at 36 months is 27% (FIGURE 2). Similarly, Mao et al followed young women in the placebo arm of an HPV 16 vaccine trial and found that all but one case of CIN 2,3 occurring after an incident HPV 16 infection developed within 12 months (FIGURE 2).¹⁵ It should be emphasized, however, that it takes almost a decade for a CIN 2,3 lesion to progress to invasive cervical cancer; therefore, it is safe to extend the screening interval to 3 years or more in women who are found to be both high-risk HPV DNA and cytology negative during routine screening.

We also have a much better understanding of the risk of being diagnosed with CIN 2,3 or cervical cancer in older, high-risk HPV DNA-positive women. In a records linkage study of Danish women who were initially cytologically negative after 3 years, CIN 2,3 or cervical cancer had been diagnosed in 6.3% of high-risk HPV-positive women.¹⁶ The cumulative detection of CIN 2,3 was 11.3% and 22.9% after 5 and 10 years of follow-up, respectively. In comparison, CIN 2,3 was diagnosed after 10 years of follow-up in only 1.9% of the HPV-negative women. A Swedish study that included all women, irrespective of cytology results, detected CIN 2,3 in 37% of women who were HPV 16 positive and 26% of those who were HPV 18 positive after 4 years of follow-up ( TABLE ).¹⁷ Importantly, in this Swedish study, CIN 2,3 lesions were detected in a substantial number of women infected with other high-risk types of HPV, including HPV 31, 33, 52, and 58. This finding contrasts with the results from a study by the National Cancer Institutes (NCI), at Kaiser, Portland, Oregon.¹⁸ In a Kaiser follow-up study of 20,810 women, the cumulative detection of CIN 3 after 10 years of follow-up was 20.7% in HPV 16-positive women >30 years of age with negative cytology; 17.7% for those with HPV 18; 1.5% for those with other high-risk types of HPV; and 0.5% for HPV DNA-negative women.

 

FIGURE 2
Cumulative detection of CIN 2,3 after incident HPV infections in two studies

HPV, human papillomavirus.
After incident HPV 16 infection (green line) and after incident HPV 16 or 18 infection (blue line).
Modified from Winer RL, et al. J Infect Dis. 2005;191:731-738 (blue line); Mao C, et al. Obstet Gynecol. 2006;107:18-27 (green line).

TABLE
Detection of CIN 2,3 or cancer

HPV status	Percent with CIN 2+*
HPV negative	0.4%
HPV 16	37%
HPV 18	26%
HPV 31	37%
HPV 33	48%
HPV 52	26%
HPV 58	30%
CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.
*Percentage of women diagnosed with CIN 2,3 or cancer during a 4-year follow-up period.
Modified from Naucler P, et al. Br J Cancer. 2007;97:129-132.

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

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

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

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

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

As soon as next year, the human papillomavirus (HPV) vaccine could transform clinical practice more than anything since the Pap smear was introduced 60 years ago.

A second large trial has shown extraordinary efficacy, and now 2 manufacturers, GlaxoSmithKline and Merck, are conducting late-phase clinical trials and working toward registering their vaccines for clinical use in 2006. Only last month, Merck and GSK signed an agreement that resolves their competing intellectual property claims—removing one more barrier to rapid commercialization.

But there are other important new developments that apply to practice now:

• Colposcopy, it appears, is far less reliable for identifying cervical intraepithelial neoplasia (CIN) 2,3 than we thought.
• The long-term risk of preterm delivery with loop electrosurgical excision procedures (LEEP) points to a need to counsel patients and consider all management options for women with CIN 1.
• The high rates of spontaneous regression of low-grade squamous intraepithelial lesion (LSIL) cytologic changes in young women are now better defined, and indicate colposcopy is not always needed.

Colposcopy not as sensitive as we thought

Pretorius R, Zhang W, Bellinson J, et al. Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse. Am J Obstet Gynecol. 2004; 191:430–434.

We need to carefully follow up whenever colposcopy does not identify a CIN 2,3 lesion. This study also reinforces the need for diagnostic excisional procedures in women with an HSIL Pap result, and who are found after colposcopy to have CIN 1 or less (FIGURE 1).

Unfortunately, colposcopy is highly subjective. Accuracy depends on training and experience. Nevertheless, it is the standard of care for identifying CIN 2,3 and invasive cervical cancer in women with abnormal Pap results. Colposcopy was thought to be a sensitive but rather nonspecific method for identifying high-grade neoplasia. A 1998 comprehensive meta-analysis estimated that colposcopy had a weighted mean sensitivity for distinguishing normal tissue from abnormal tissue of 0.96 (95% confidence interval [CI], 0.95-0.97) and a weighted mean specificity of 0.48 (95% CI, 0.47-0.49).¹ This means that colposcopy would miss a biopsy-confirmed cervical abnormality in only about 4% of patients. However, more recent follow-up studies have reported much higher false negative rates for colposcopy.

Pretorius and colleagues studied women enrolled in a cervical cancer screening trial conducted in Shanxi, China. The colposcopy in this study was performed by attending gynecologic oncologists who worked closely with a team of US-based gynecologic oncologists. The women in the study had biopsies taken of all areas classified as abnormal by colposcopy. In addition, random 4-quadrant cervical biopsies were obtained from colposcopically normal regions of the cervix.

A total of 364 women with a satisfactory colposcopy and biopsy-confirmed CIN 2 or greater lesions were identified. Even though all 364 women had a satisfactory colposcopic examination, only 57.1% of the women with biopsy-confirmed CIN 2 or worse were detected by the colposcopically-directed biopsy; the remaining 42.9% were detected by the random biopsies of colposcopically normal-appearing tissue. The lesions that were missed by colposcopy tended to be smaller than those identified by colposcopy and were more frequently CIN 2 rather than CIN 3 lesions.

This study also evaluated the role of endocervical curettage, and found that even among women with a satisfactory colposcopic examination, a significant proportion (5.5%) of cases of CIN 2,3 or worse were detected only by using endocervical curettage.

FIGURE 1 Repeat colposcopy and biopsy may reveal high-grade lesion

Low-grade cervical intraepithelial neoplasia (CIN 1) of the cervix. This young woman has a well-defined acetowhite lesion of her cervix that was diagnosed as a CIN 1 on cervical biopsy. In many such cases, repeat colposcopy and biopsy identifies an area of high-grade lesion that was missed at the initial colposcopy.

REFERENCE

1. Mitchell MF, Schottenfeld D, Tortolero-Luna G, Cantor SB, Richards-Kortum R. Colposcopy for the diagnosis of squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;91:626-631.

LEEP raises risk of preterm birth

Sadler L, Saftlas A, Wang W, et al. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA. 2004;291:2100-2106.

We need to counsel women that LEEP will increase their risk for preterm premature rupture of membranes (PPROM) and preterm delivery. We must recognize that it is desirable to follow, rather than treat, biopsy-confirmed CIN 1, and to limit the depth of excision to 1 cm or less whenever possible.

 

Although Consensus Guidelines state that both ablative and excisional methods are acceptable forms of managing women with satisfactory colposcopy and CIN 2,3, for most clinicians, LEEP has completely replaced laser ablation and cryotherapy for treatment of CIN.¹ Because LEEP is so widely utilized, its effects on fertility and preterm delivery, as well as other adverse pregnancy outcomes, are of great concern.

LEEP became widely adopted since its introduction in the early 1990s because it yields a tissue specimen for histological evaluation and is less expensive and easier to perform than laser ablation.

Unfortunately, most studies of the impact of LEEP on fertility and pregnancy have been limited or inconclusive, and most lacked statistical power to detect a doubling of risk. The New Zealand study conducted by Sadler and colleagues—a large retrospective cohort study—compared delivery outcomes of 426 untreated women with 652 women treated by laser conization, laser ablation, or LEEP. Women who had LEEP or laser cone treatment were at significantly increased risk of rupture of membranes before 37 weeks’ gestation. Notably, in women who had undergone a LEEP, the adjusted relative risk (RR) for PPROM was 1.9 (95% CI, 1.0-3.8) compared to the untreated women. Laser ablation did not increase risk (RR 1.1). This study demonstrate that women who have undergone LEEP have almost twice the risk for PPROM as untreated women, should be of concern to all gynecologists.

Risk of both PPROM and preterm delivery increased as depth of cervical tissue removed increased. Women in whom 1 cm or less of tissue was excised had no increased risk of PPROM or preterm birth; women in whom more than 1.7 cm of tissue was excised had an adjusted relative risk of 3.6 (95% CI, 1.8-7.5).

In a Canadian study published only last month, Samson and colleagues found PPROM was almost 4 times more common among women who had had a LEEP.²

REFERENCES

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

2. Samson S, Bentley JR, Fahey T, McKay D, Gill G. The effect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol. 2005;105:325-332.

LSIL cytology meaningless?

Moscicki A, Shiboski S, Hills N, et al. Regression of low-grade squamous intraepithelial lesions in young women. Lancet. 2004;364:1678–1683.

This study shows just how meaningless LSIL cytology is in young women—and it portends changes in the next Consensus Guidelines. Colposcopy for all adolescents and young women is unwarranted, the authors stated. They recommend monitoring with repeat cytology instead.

For over a decade it has been widely appreciated that many CIN 1 lesions spontaneously regress in the absence of therapy.¹ Based on what we recently learned from natural history studies of HPV, we know that the majority of LSIL cytology results and biopsy-confirmed CIN 1 lesions represent nothing more than the morphological manifestation of a productive HPV infection.² HPV infections, including those with high-risk types of HPV, are typically self-limited (FIGURE 2). In approximately 90% of women, HPV shedding stops spontaneously within 24 months.

However, in the United States, most women with LSIL undergo colposcopy, and many clinicians continue to treat women with biopsy-confirmed CIN 1. These approaches do correspond to the most recent Consensus Guidelines, which recommend colposcopy for women with LSIL, and state that follow-up with treatment, as well as treatment with ablative or excisional methods, are acceptable management options for women with CIN 1.³

Regarding adolescents with LSIL, the guidelines made an exception to performing a colposcopy. For these patients, an acceptable management option is follow-up without initial colposcopy, using a protocol of repeat cytological testing at 6 and 12 months, or HPV testing at 12 months.

 

To better define the best way to manage young women with LSIL, Moscicki and colleagues followed a cohort of 204 young women (ages 13 to 22 years), who had an LSIL Pap result, for up to 80 months (median 61 months). HSIL cytology (N=6) or biopsy-confirmed CIN 2,3 (N=17) was found in only 11.3% of the women. After 36 months, only 6% had persistent LSIL.

The remainder had had 3 consecutive negative Pap results, and the median time to developing the first of 3 negative Pap results was only 8 months.

FIGURE 2 Even high-risk HPV types usually abate in young women

Liquid-based cytology specimen diagnosed as low-grade squamous intraepithelial lesion (LSIL), with marked koilocytosis with multinucleation, perinuclear halos, and nuclear atypia. These features typify productive HPV infection that usually regresses spontaneously in young women.

REFERENCES

1. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP. Natural history of cervical squamous intraepithelial lesions: a meta-analysis. Obstet Gynecol. 1998;92:727-735.

2. Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003;348:489-490.

3. Wright TC, Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.

Bivalent vaccine vanquishes HPV

Harper D, Franco E, Wheeler C, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757–1765.

HPV vaccine may be registered for clinical use next year. Since two-thirds of cervical cancers are caused by only 2 types of high-risk HPV—HPV 16 and HPV 18—a vaccine that prevents infection with HPV 16 and 18 could reduce cervical cancer and high-grade precursor lesions by more than half.

Extraordinary efficacy—100% against persistent infections and 91.6% against incident HPV 16 or 18 infections—was found in this Phase II trial of a bivalent HPV vaccine made by GlaxoSmithKline—the second such trial to show high efficacy for an HPV vaccine. Merck found high efficacy for its monovalent vaccine. Both companies are conducting Phase III registration trials.

Harper and colleagues observed these efficacy rates in women who took all their scheduled vaccinations. They used bivalent HPV 16 and 18 vaccine in a study of 1,113 women randomized to receive 3 doses of vaccine or placebo over a 6-month period. All were followed for up to 27 months.

The vaccine was also highly effective against cytological abnormalities associated with HPV 16 or 18 and was generally safe, well tolerated, and highly immunogenic.

In 2002, a Phase II trial of a monovalent HPV 16 vaccine produced by Merck demonstrated efficacy of 100% over 18 months in preventing persistent HPV 16 infection or CIN associated with HPV 16.¹

Both companies’ vaccines consist of viral-like particles that are made by producing recombinant L1 capsid protein of the specific HPV type and then allowing the recombinant L1 capsid proteins to assemble into a structure that appears identical to the native virus, but lacks infectious DNA.

Each year, 470,000 women develop invasive cervical cancer, and 230,000 die, globally. Vaccination is a particularly attractive strategy for preventing cervical cancer in developing countries, where less than 5% of women have ever been screened.

Yet these numbers do not begin to take into account the huge costs and burden of disease due to noninvasive cervical cancer precursors and abnormal screening cytology. In the United States alone, we spend up to $6 billion a year on prevention and treatment of cervical cancer.

The author reports no financial relationships relevant to this article.

REFERENCE

1. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-1651.

A 2001 adjustment in the terminology used to report cytology results was the first of 4 recent advancements that, in sum, have fundamentally changed how we interpret and follow-up Pap smears. Another breakthrough in cervical disease reveals clear potential for a vaccine for human papillomavirus (HPV). This Update on Cervical Disease reviews these pivotal developments:

• The 2001 revision of the Bethesda System—also known as Bethesda 3—for reporting cervical cytologic results.
  
• The 2001 consensus guidelines on managing women with abnormal cytology and cer-vical cancer precursors.
  
• Interim guidance on the use of HPV DNA testing as an adjunct to cervical cytology for screening.
  
• Findings of the National Cancer Institute’s ASCUS/LSIL Triage Study (ALTS).
  
• A proof-of-principle trial demonstrating the potential clinical utility of a vaccine for HPV type 16 (HPV-16) in young adults.
  

New terms aim to reduce unnecessary repeat Paps

Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.

By deleting a few categories, changing several definitions, and adding new information to the report, the new Bethesda System for reporting results of screening cytology has created a simpler, more precise, and more helpful report.

Elements of the widely utilized 1991 system were believed to cause confusion and lead to unnecessary repeat testing, as well as undue concerns and expenses; these have been refined. Key original features that served well, however, remain. For example, results are still shown in 3 distinct sections: specimen adequacy; general interpretation of normal or abnormal; and specific interpretation, or type of abnormality, if present.

Simpler classifications with notes added when indicated are a step forward from the standpoint of physicians and patients alike.

• Specimen adequacy is now either “satisfactory” or “unsatisfactory” for evaluation. The confusing category “satisfactory but limited by …” was eliminated because it seemed to lead to many unnecessary repeat Pap tests. Under the old system, specimens were categorized as “satisfactory but limited by …” for any number of reasons, including lack of a transformation-zone component, partially obscuring blood, inflammation, or poor presentation. Such specimens are now classified as “satisfactory for evaluation,” and a statement describing any flaws in the specimen is added.
  
• “Benign cellular changes,” a classification that confused patients, was also appropriately eliminated. Cases that fell into that category under the old system are now classified as “negative for intraepithelial lesion or malignancy” (ie, normal), and include a statement explaining that organisms, reparative changes, radiation effect, atrophy, or other conditions are present.
  

“Atypical squamous cells of undetermined significance” (ASCUS), which previously described all nondiagnostic or borderline squamous cytologic abnormalities, was subdivided in an attempt to reduce the number of cases inappropriately classified as having borderline changes.

ASCUS was changed to “atypical squamous cells” (ASC), with 2 subcategories: “undetermined significance” (ASC-US) and “suggestive of a high-grade squamous intraepithelial lesion” (ASC-H) (Atypical squamous cells: The case for HPV testing”

A 2001 adjustment in the terminology used to report cytology results was the first of 4 recent advancements that, in sum, have fundamentally changed how we interpret and follow-up Pap smears. Another breakthrough in cervical disease reveals clear potential for a vaccine for human papillomavirus (HPV). This Update on Cervical Disease reviews these pivotal developments:

• The 2001 revision of the Bethesda System—also known as Bethesda 3—for reporting cervical cytologic results.
  
• The 2001 consensus guidelines on managing women with abnormal cytology and cer-vical cancer precursors.
  
• Interim guidance on the use of HPV DNA testing as an adjunct to cervical cytology for screening.
  
• Findings of the National Cancer Institute’s ASCUS/LSIL Triage Study (ALTS).
  
• A proof-of-principle trial demonstrating the potential clinical utility of a vaccine for HPV type 16 (HPV-16) in young adults.
  

New terms aim to reduce unnecessary repeat Paps

Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.

By deleting a few categories, changing several definitions, and adding new information to the report, the new Bethesda System for reporting results of screening cytology has created a simpler, more precise, and more helpful report.

Elements of the widely utilized 1991 system were believed to cause confusion and lead to unnecessary repeat testing, as well as undue concerns and expenses; these have been refined. Key original features that served well, however, remain. For example, results are still shown in 3 distinct sections: specimen adequacy; general interpretation of normal or abnormal; and specific interpretation, or type of abnormality, if present.

Simpler classifications with notes added when indicated are a step forward from the standpoint of physicians and patients alike.

• Specimen adequacy is now either “satisfactory” or “unsatisfactory” for evaluation. The confusing category “satisfactory but limited by …” was eliminated because it seemed to lead to many unnecessary repeat Pap tests. Under the old system, specimens were categorized as “satisfactory but limited by …” for any number of reasons, including lack of a transformation-zone component, partially obscuring blood, inflammation, or poor presentation. Such specimens are now classified as “satisfactory for evaluation,” and a statement describing any flaws in the specimen is added.
  
• “Benign cellular changes,” a classification that confused patients, was also appropriately eliminated. Cases that fell into that category under the old system are now classified as “negative for intraepithelial lesion or malignancy” (ie, normal), and include a statement explaining that organisms, reparative changes, radiation effect, atrophy, or other conditions are present.
  

“Atypical squamous cells of undetermined significance” (ASCUS), which previously described all nondiagnostic or borderline squamous cytologic abnormalities, was subdivided in an attempt to reduce the number of cases inappropriately classified as having borderline changes.

ASCUS was changed to “atypical squamous cells” (ASC), with 2 subcategories: “undetermined significance” (ASC-US) and “suggestive of a high-grade squamous intraepithelial lesion” (ASC-H) (Atypical squamous cells: The case for HPV testing”

A 2001 adjustment in the terminology used to report cytology results was the first of 4 recent advancements that, in sum, have fundamentally changed how we interpret and follow-up Pap smears. Another breakthrough in cervical disease reveals clear potential for a vaccine for human papillomavirus (HPV). This Update on Cervical Disease reviews these pivotal developments:

• The 2001 revision of the Bethesda System—also known as Bethesda 3—for reporting cervical cytologic results.
  
• The 2001 consensus guidelines on managing women with abnormal cytology and cer-vical cancer precursors.
  
• Interim guidance on the use of HPV DNA testing as an adjunct to cervical cytology for screening.
  
• Findings of the National Cancer Institute’s ASCUS/LSIL Triage Study (ALTS).
  
• A proof-of-principle trial demonstrating the potential clinical utility of a vaccine for HPV type 16 (HPV-16) in young adults.
  

New terms aim to reduce unnecessary repeat Paps

Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114-2119.

By deleting a few categories, changing several definitions, and adding new information to the report, the new Bethesda System for reporting results of screening cytology has created a simpler, more precise, and more helpful report.

Elements of the widely utilized 1991 system were believed to cause confusion and lead to unnecessary repeat testing, as well as undue concerns and expenses; these have been refined. Key original features that served well, however, remain. For example, results are still shown in 3 distinct sections: specimen adequacy; general interpretation of normal or abnormal; and specific interpretation, or type of abnormality, if present.

Simpler classifications with notes added when indicated are a step forward from the standpoint of physicians and patients alike.

• Specimen adequacy is now either “satisfactory” or “unsatisfactory” for evaluation. The confusing category “satisfactory but limited by …” was eliminated because it seemed to lead to many unnecessary repeat Pap tests. Under the old system, specimens were categorized as “satisfactory but limited by …” for any number of reasons, including lack of a transformation-zone component, partially obscuring blood, inflammation, or poor presentation. Such specimens are now classified as “satisfactory for evaluation,” and a statement describing any flaws in the specimen is added.
  
• “Benign cellular changes,” a classification that confused patients, was also appropriately eliminated. Cases that fell into that category under the old system are now classified as “negative for intraepithelial lesion or malignancy” (ie, normal), and include a statement explaining that organisms, reparative changes, radiation effect, atrophy, or other conditions are present.
  

“Atypical squamous cells of undetermined significance” (ASCUS), which previously described all nondiagnostic or borderline squamous cytologic abnormalities, was subdivided in an attempt to reduce the number of cases inappropriately classified as having borderline changes.

ASCUS was changed to “atypical squamous cells” (ASC), with 2 subcategories: “undetermined significance” (ASC-US) and “suggestive of a high-grade squamous intraepithelial lesion” (ASC-H) (Atypical squamous cells: The case for HPV testing”