1. Module 2: Cervical Cancer Screening Guidelines, 2012

3. Background and Need for Cervical Cancer Screening

4. The goals of screening are to prevent cervical cancer and the morbidity and mortality associated with a cancer diagnosis. The only way we currently have of achieving those goals is to find those lesions that have malignant potential—defined as cervical intraepithelial neoplasia (CIN) 3. At the same time that we look for those high-grade lesions, we want to reduce the potential of overdiagnosing and overtreating minor lesions most likely to regress on their own.

5. Module 1 explained that almost all cervical cancer is caused by the human papillomavirus (HPV). Most women diagnosed with HPV by sensitive molecular testing will become HPV-negative within 6 to 12 months, indicating immune suppression of HPV. It is likely that most, if not all, women infected with HPV have some viral vaginal or cervical cell expression of HPV but are not aware of it, and the virus is subsequently suppressed.
When CIN 1 is detected, spontaneous regression can be expected in about 70% of cases within 6 to 24 months. About 10% of women diagnosed with CIN 1 after colposcopy based on cytology that finds a low-grade squamous intraepithelial lesion (LSIL) will eventually develop CIN 2 or 3—not as direct progression from CIN 1, but rather as a separate monoclonal high-grade cellular change.
Some women will develop CIN 2 or 3 directly from HPV infection without detection of a preexisting low-grade lesion. It used to be thought that there was a linear progression from CIN 1 to 2 to 3 to cancer. Now, it appears that some high-grade lesions (CIN 2/3) may arise de novo as a result of molecular makeup. Approximately 40% of diagnosed CIN 2 resolves spontaneously, but most CIN 3 persists. After an average of 10 to 13 years, CIN 3 may progress to invasive cervical cancer as spontaneous mutations accumulate, eventually making the cell immortal. Because of the long period of time usually required for the HPV-infected cell to become a cancer, we are able to screen for and manage precancerous cervical lesions, preventing invasive cervical cancer.

6. Many sources emphasize that being rarely or never screened is the major contributing factor to most cervical cancer deaths today.

7. Women who are most likely not to be screened or undergo infrequent screening are often minorities, of low socioeconomic status, foreign-born and living in the United States less than 10 years, or have no regular source of health care. These findings come from data from a variety of reputable US national resources, including the US Census and the Centers for Disease Control and Prevention (CDC).

8. This slide shows the “swiss cheese” theory of system failures leading to a diagnosis of cervical cancer. This theory illustrates how, even though we have several opportunities to identify and prevent cervical cancer, it is possible for a woman to bypass all of them. The primary reason that women get cervical cancer is that they do not present for screening at all or are only rarely screened at irregular intervals. Second, health care providers do not screen women during routine office visits. Even when there is screening, there may be no follow-up or inadequate follow-up. Finally, some women may either refuse appropriate therapy or delay it, or they may be lost to follow-up. The end result is invasive cervical cancer.
Courtesy of Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD

9. These failings are demonstrated by the results of a retrospective study conducted by researchers at Kaiser Northern California who evaluated the histories of 833 women diagnosed with cervical cancer in a recent time period.1 More than half of the women never had cervical cytology despite the routine availability of this service to members without additional charge. Eighty percent visited the clinic at least once but were not scheduled for a cytology test. About one third of the women had one or more false-negative cytology reports prior to the diagnosis, even though most of the cytology samples were satisfactory for evaluation. Another 13% had an abnormal report but failed to receive adequate follow-up, either because they were not notified or they failed to follow through when appropriately advised.
The clinical implications of this analysis are applicable to nearly all medical settings. First, provision of a service does not guarantee that it will be used even if cost is not an issue and the patient attends the clinic for other reasons. Second, false-negative results do occur even when the test specimen is satisfactory. Third, abnormal test follow-up notification and reminder systems must be as “fail-proof” as possible; even then, some patients will not receive follow-up as advised.

10. These data come from the CDC’s National Health Interview Survey
These data come from the CDC’s National Health Interview Survey.2 The highest-risk groups reporting inadequate screening are women who are uninsured and immigrants who have been in the United States less than 10 years. These groups of women could benefit most from screening with a test that has both high sensitivity and specificity, because they may only be screened rarely. Among some foreign-born women, even those with extensive education and economic affluence, there are cultural barriers to screening.

11. These 2007 data from CDC demonstrated that screening rates were highest among women ages 25 to 44 years.3 In all age groups, there was a direct correlation between prevalence of screening and education level attained. Women with higher education levels were more likely to be screened than women with less education. It is clear that screening rates are affected by education levels, insurance access, and country of birth. Screening rates in the United States have improved considerably during the past two decades, but approximately 18% of women are not screened at all or not often enough to provide adequate protection.

12. In recent decades, concerns about the sensitivity of conventional cervical cytology led to the evaluation of alternatives.
Liquid-based cytology (LBC) was first introduced into clinical practice following licensing by the US Food and Drug Administration (FDA) in 1996 of a thin-layer cytology system.
An HPV test using hybrid capture technology was approved by the FDA in 1999 for management of atypical squamous cells of undetermined significance (ASC-US) and in 2003 as a cotest with cytology for women ages 30 and over. A newer signal amplification HPV DNA test and type-specific test for HPV 16 and 18 were licensed by the FDA for clinical use in early 2009.
The FDA licensed a quadrivalent HPV vaccine in June This vaccine was approved for use in girls and women 9 to 26 years of age and included protection against two high-risk and two low-risk HPV types. In October 2009, the FDA licensed a bivalent HPV vaccine for the prevention of two high-risk types for use in girls and women up to age 25. A new vaccine was approved and made available in early 2015 that protects against nine HPV types.
Tests using other biomarkers, such as mRNA and p16, to measure increased risk for cervical cancer have also been introduced to the market.

13. Persistent HPV infection leads to persistent CIN, which can progress to cancer. Although probably less than half of CIN 3 lesions will progress to cancer, we do not have the ability at the present to determine which ones have that malignant potential. Therefore, CIN 3 requires treatment. In women beyond reproductive age, CIN 2 can be treated without concern for the effects on pregnancy.

14. Development of Consensus Guidelines

15. In 2011, the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology held a conference to discuss new guidelines for cervical cancer screening.

17. Twenty-one organizations participated in the discussion and voting.

18. Working groups consisted of experts in the field of cervical cancer and HPV and met regularly via teleconference. Each group was assigned a topic and reviewed the evidence. The quality of evidence of each article was graded. The outcomes and recommendations were also categorized.

19. These topics were addressed in the development of the screening guidelines.

20. In developing the guidelines, the WG members agreed to a number of assumptions.
No screening test is perfect and there will always be some degree of cancer risk with any type of screening. Patients and providers should be aware of this risk.
Cytology alone at 2- to 3-year intervals has been considered the standard of care for some years, and screening strategies that achieve equivalent or better outcomes would be acceptable.
Similar cancer risks should be managed in a similar way—that is, if two different cytology results have the same risk of CIN 3+, they should be managed similarly.

21. Both conventional cytology (glass slide) and LBC are about equal
Both conventional cytology (glass slide) and LBC are about equal. However, LBC may allow for easier HPV testing. Only those HPV tests approved by the FDA should be used. There are some laboratory-developed tests available, but their results cannot be extrapolated to these guidelines. Even among the FDA-approved tests, there may be variability in performance outcomes.

22. CIN 1 is generally not treated unless it persists for at least 2 years and the patient desires treatment.
CIN 3 has been chosen to represent a true cancer precursor.
CIN 2 s often a difficult diagnosis to make histologically, with review pathologists downgrading some lesions to CIN 1 and upgrading others to CIN 3. For this reason, the 2012 Lower Anogenital Squamous Terminology Project recommended changing the categories from three tiers (CIN 1,2,3) to two (low grade and high grade).4 The project also recommended the adjuvant use of p16 staining to help differentiate those CIN 2 lesions that act more like CIN 1 from those that act more like CIN 3 with malignant potential.

24. Colposcopy is the most measureable harm; financial impact was not measured.

25. Although there is conflicting evidence surrounding reproductive outcomes after cervical treatment, a number of studies have shown harms, especially after multiple treatments.5, 6 If women of reproductive age are subjected to treatment for minor lesions, their risk of having multiple treatments over time increases. Some evidence from Europe on pregnancy outcomes may not be generalizable to the United States, because they tend to use larger loop sizes, therefore removing more tissue.

26. The conference was held in 2011; the guidelines were published in 2012.

27. 2012 Cervical Cancer Screening Guidelines7,8

28. 28

29. A common question is whether women who have never had intercourse should be screened for cervical cancer at age 21. In such cases, a good sexual history must be obtained. Has the woman ever had sex involving digital, oral, or genital contact? Does she have a history of sexual assault or abuse? Even many women who have sex with women or their partners may have had heterosexual contact at some point in their lives. While a 21-year-old woman with no sexual contact may opt to forego screening, it is important for her to be educated on the relatively easy transmission of HPV and its role in genital and other cancers.
These screening guidelines do not apply to other at-risk groups. For women with HIV, consult the CDC’s Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.9

30. Invasive cervical cancer prior to age 21 is extremely rare, but there is a high rate of HPV DNA detection and subsequent occurrence of equivocal and low-grade cytology reports in young women. Waiting until age 21 to screen reflects the concern for adverse outcomes associated with the follow-up of minor cytological abnormalities found in girls and young women of reproductive age. The age-specific incidence of cervical cancer noted here supports the recommendation not to begin screening until age 21. Even though some clinicians may be concerned that delaying screening until age 21 may result in missing cervical cancer, the evidence shows how low the risk of cervical cancer is in young women and girls. Among those age 19 and younger, this risk is 1 case per million women per year.10

31. There are many other adolescent health needs that can be addressed at a wellness visit that do not include cervical cytology.
If an adolescent presents with signs of cervical cancer, such as bleeding after intercourse or a friable mass on the cervix, a cytology test might be part of the diagnostic workup. However, it is not considered a screening test if the patient is symptomatic.

32. For women ages 21-24, HPV testing is not recommended for those who have ASC-US cytology.11
For women 25 and above, HPV testing is preferred for those with ASC-US cytology, known as reflex testing.
Visit the ASCCP website for a webinar on the benefits and harms of using HPV testing to screen women years old. It provides a more complete understanding of this issue.

33. Rationale for Longer Cytology Screening Intervals12
Few studies address the best interval for cytology-based screening in women under 30, and most are modeling studies. Cytology is known to have low sensitivity. However, in one study, the risk of high-grade disease (CIN 3+) was no different between 2-year and 3-year testing intervals after the last negative test result.12 In this age group, studies found an incremental rise in cancer risk as the interval from the last negative cytology moved beyond 3 years. Extending the screening interval beyond 3 years is not recommended.

34. In the guidelines, the number of colposcopies was used as a surrogate for harms in balancing the benefit and burden of screening. Issues of anxiety, discomfort, stigmatization of an STI, overdiagnosis, and overtreatment are associated with colposcopy. These modeling studies show a significant increase in colposcopies when women are screened annually.13, 14

35. These data from CDC’s National Health and Nutrition Examination Survey show the US prevalence of HPV by age and HPV type.15 The prevalence of HPV is high in younger women. However, as we saw on a previous slide, cervical cancer is uncommon in women under 30, so HPV testing is of lesser value in younger women. Additional prevalence data from Manchester, England, clearly demonstrate that women age 30 and over have the lowest rate of HPV infection for all HPV types, and more importantly, for high-risk types.16

36. As the previous slides demonstrated, the rates of HPV infection are high in younger women, but in most of those cases—up to 90%—the infection will resolve without consequence.17 Overdiagnosis of a transient infection has potential risks.

37. As we have seen, the rates of transient HPV infection drop in this age group. So, using an HPV test in conjunction with cytology to identify women with persistent infection is of greater benefit.

38. Not only does adding HPV testing to cytology detect more prevalent disease when the HPV test is positive, it also reduces the amount of subsequent disease found when the HPV test is negative. HPV testing adds greater sensitivity to the results of cytology. Another benefit of cotesting is the identification of adenocarcinoma and adenocarcinoma in situ (AIS). Because these lesions tend to be located in the endocervical canal, they can be more difficult to detect, and cytology alone has been less effective at decreasing the incidence of invasive adenocarcinoma. Lengthening the intervals between screening (when results are negative) decreases the detection of minor cytologic abnormalities that have no clinical consequence.

39. There may be reasons that cotesting is not feasible or available, and in such cases, cytology alone at 3-year intervals remains effective. The trade-off is the increased detection of minor abnormalities that have no clinical consequence.

40. Because a cotest that is negative for abnormal cytology and HPV has a high negative predictive value (NPV), it is safe to use a longer screening interval. There is no value in doing both tests at frequent intervals as the harms—detection of low-grade transient lesions leading to colposcopies, biopsies, and overtreatment—outweigh the benefits.

41. This slide shows the high rate of clearance of HPV infections among women who are HPV-positive. In this natural history study of 10,000 women ages 30 and over, approximately 60% of HPV-positive women were found to be HPV-negative within 12 months (shown in green).18 Waiting 12 months to repeat the cytology and HPV test allows for spontaneous resolution of the majority of HPV infections that were destined to be transient. Only those women with persistent high-risk HPV are referred for colposcopy. Among this group, 35% remained HPV-positive after 12 months (shown in blue). However, it is clear that with increasing persistence, the risk for developing precancer and cancer, shown in red, increases.

42. These recommendations reflect the screening guidelines published in July Data from the ASCUS/LSIL Triage Study (ALTS) for Cervical Cancer showed that the 2-year cumulative risk of CIN 3+ after a finding of ASC-US in women who were HPV-negative was less than 2%, which was below the threshold for colposcopy. Therefore, it was recommended that these women be screened at the same interval as women with negative cotests. Subsequently, new data became available, and the recommendation was changed, as shown on the next slide.

43. The 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors take into account the Kaiser expanded dataset, which found the absolute risk of CIN 3+ was low after an ASC-US/HPV-negative result.19 However, the risk was more comparable to CIN 3+ risk with negative cytology alone (for which a 3-y interval was recommended) than negative cotesting results (for which a 5-y interval was recommended). So, the recommendation was changed in keeping with the goal of treating similar risks with similar management.
It was also determined that, although rare, women who had a cotest result of ASC-US/HPV-negative at age 65 (when they could have been eligible for exiting screening) had a higher rate of cancer later on, and so it was recommended that screening continue.

44. If the cotest result is cytology-negative/HPV-positive, there are two options for management. Repeat both tests in 12 months or order genotyping to look for the presence of the high-risk HPV types 16 and 18.

45. Option 1: The prevalence of women testing cytology-negative/HPV-positive ranges from 3.4% to 8.2% in women over 30. (In the Kaiser Permanente Northern California data, the prevalence was 3.6%.) This finding, however, is the most common abnormal screening result obtained from cotesting. The good news is that about 50% of these HPV infections clear within 6 months, and 75% are clear within 1 year, indicating transient infection.
Routine screening is currently defined as screening every 5 years with cytology/HPV cotesting or every 3 years with cytology alone.

46. Option 2: If you have access to genotyping for HPV types 16 and/or 18, use option 2. If either or both are positive, the woman should be referred for colposcopy, as the risk for prevalent disease is clearly higher. HPV 16 confers a greater risk than HPV 18 for CIN 3+. If the woman is negative for HPV types 16 and 18, repeat the cotest in 12 months.

47. Even with an HPV-positive result, negative cytology indicates a lower risk than cytological reports of ASC-US and LSIL. A considerable number of HPV infections will clear within 12 months, including those caused by high-risk types.

48. If a woman has been treated for CIN 2+, surveillance should continue for 20 years, even if that means follow-up beyond age 65. Evidence of adequate negative screening is defined as 3 negative cytology tests or 2 negative cotests within the 10 years before ceasing screening, with the most recent test occurring within the past 5 years. If records or knowledge of her screening history exists, screening can continue beyond age 65 to meet these criteria.
Remember that a result of ASC-US/HPV-negative requires continued screening and should not be considered a “negative” result.

49. The natural history of HPV is not affected by the age at which a woman acquires it. Most infections will be transient, as in younger women. The transformation zone in older women is smaller and less vulnerable to HPV infection. Because cervical cancer develops after years of persistent infection, continuing to screen older women, primarily those with a history of consistently normal cytology results, would prevent very few cervical cancers.

50. High-grade cervical disease is rare in older women who have been screened regularly.19, 20 Transient HPV infections can occur, even without recent genital contact, but are unlikely to cause clinical disease.

51. If a hysterectomy was performed for benign disease, there is no reason to continue screening with cytology or HPV testing. Vaginal cancer is an uncommon malignancy.

52. Screening the general population for vaginal cancer is not recommended because the disease is so rare. There are some vaginal cancers for which screening would not help, i.e., sarcomas and metastatic disease. There is low risk of cytologic abnormalities in the vagina; in one study, the positive predictive value of cuff cytology for cancer was zero.21, 22
In women with a history of CIN 2+ who have had a hysterectomy, there may be an increased risk of vaginal cancer, but the data are limited. There is no approved indication for screening with HPV testing in the vagina.

54. The rate of HPV vaccination coverage in this country is low, and often women are unsure of their vaccine status or whether they completed the 3-dose regimen. Until 2015, HPV vaccines only protected against high-risk HPV types 16 and 18, so infection with other high-risk types could occur. Many women are being vaccinated after HPV exposure. Vaccination was shown to be very effective during clinical trials among unexposed women.23 However, it remains a challenge to vaccinate young women and men before they become sexually active and exposed to the virus.

56. In 2012 when these guidelines were published, primary screening with HPV had not been reported in a U.S. population and was not approved by the FDA, so concerns about the approach were raised.

57. In 2014, the results from the ATHENA trial showed the benefit of primary HPV screening among a cohort of women ages 25 and older. Nevertheless, questions still exist about appropriate follow-up of abnormal results and modes and intervals of future screening.25

58. Only one of the four current FDA-approved HPV tests has been approved for primary screening. This slide shows the algorithm for primary screening with HPV testing. If the results of HPV testing are positive for HPV types 16 or 18, colposcopy is recommended. If they are positive for any of the other high-risk HPV types, cytology is recommended to determine whether the woman should be referred for colposcopy or follow-up in 12 months. If the results are negative for high-risk types, routine screening is recommended in 3 years. 

59. As of 2012, for the first time, the ACS, ASCCP, ASCP, and the USPSTF25 have the same screening guidelines with only minor wording differences. This harmonization should simplify recommendations and streamline care across clinical settings. Primary HPV screening is not included on this chart.

60. While we may continue to debate best practices in screening, the biggest challenge remains screening all women for cervical cancer.

64. References (continued)