Cervical cancer screening

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.