The American Society for Colposcopy and Cervical Pathology (ASCCP) National Consensus Conference for the Management of Women With Cervical Cytological Abnormalities and Cervical Cancer Precursors was held on the National Institutes of Health campus in Bethesda, Md, September 6–8, 2001. The conference was attended by 121 representatives from 29 national organizations interested in cervical cancer screening issues. For the first time, guidelines for the management of women with abnormal cervical cytology, developed from evidence-based literature, were presented to delegates from the majority of organizations with interest in cervical cancer screening, voted on, and revised when necessary to achieve a majority two-thirds approval. This development of consensus-approved guidelines is likely to be considered one of the most important milestones to date in the management of women with abnormal cervical cytology. The timing of this Consensus Conference resulted from the convergence of many different factors, including new cytologic terminology developed at the Bethesda 2001 workshop and publication of the enrollment data from the National Cancer Institute's Atypical Squamous Cells of Undetermined Significance (ASC-US)/Low-Grade Squamous Intraepithelial Lesions (LSIL) Triage Study, otherwise known as ALTS. Additionally, new preliminary longitudinal ALTS data provided much of the information on the natural history of abnormal Papanicolaou tests and cervical intraepithelial neoplasia (CIN), as well as data on the performance of both new liquid-based cytology and human papillomavirus (HPV) DNA testing in the management of women following colposcopy. The result was a large database of new information that provided the foundation for the ASCCP Consensus Conference.

This article covers only the recommendations of the ASCCP Guidelines that were based in large part on the results of the ALTS trial. Therefore, the focus is on the management of women with equivocal (ASC-US) and low-grade (LSIL) cytologic abnormalities. Management of women with these cytologic abnormalities has been particularly problematic, because individually these women are at least risk for CIN 3 and cancer, yet their sheer numerical dominance ensures that they account for the majority of high-grade CIN detected in the United States in the follow-up of abnormal cervical cytology. Data from ALTS confirmed that women with ASC-US could be safely managed by any of the conventional approaches (repeat Papanicolaou test, immediate colposcopy, or HPV testing), but that the preferred management approach for women having an ASC-US report from liquid-based cytology was to assess the patient's risk by testing for HPV. Additionally, longitudinal ALTS data determined that repeat liquid-based cytology at 6 and 12 months and an HPV test at 12 months were nearly equivalent options in the follow-up of women referred for HPV-positive ASC or LSIL, yet not found to have CIN 2+ at initial colposcopy. Therefore, all follow-up recommendations for women with CIN 1 or lower postcolposcopy findings include these 2 options. The data and the recommendations for the management of ASC-US, ASC cannot exclude high-grade squamous intraepithelial lesion, and LSIL are discussed.

The abnormal morphologic changes described by The Bethesda System include atypical squamous cells (ASC; both ASC of undetermined significance [ASC-US] and ASC cannot exclude high-grade squamous intraepithelial lesion [ASC-H]), atypical glandular cells (AGC), low- and high-grade squamous intraepithelial lesion (LSIL and HSIL), and squamous carcinoma and adenocarcinoma.1 Most studies on the use of human papillomavirus (HPV) testing in the clinical management of women with abnormal cervical cytology have concentrated on the utility of the test for the management of women with ASC-US2–4 and women with LSIL,5 and the new guidelines have recognized that HPV testing has a significant role both in the management of women with equivocal cytology and in the follow-up of women with either HPV-positive ASC-US or LSIL who do not have cervical intraepithelial neoplasia (CIN) 2 or higher pathology at initial colposcopy.6 In contrast, use of HPV testing for the triage of women with either LSIL (except under special circumstances) or AGC cytology is not presently recommended, either because of the very high rate of HPV positivity (LSIL)5 or a lack of sufficient data to ensure utility (AGC).6 This article focuses on the new American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus Guidelines for the Management of Women With Cervical Cytological Abnormalities and Cervical Cancer Precursors,6 particularly in relation to the areas in which HPV testing plays a prominent role, and to the data that provided the evidence that substantiated the recommendations.

It has been estimated that the cervical cancer screening program in the United States costs US $6–7 billion annually, with a considerable proportion being spent on women with the following low-grade cytologic abnormalities: ASC-US, AGC, and LSIL.7 Although each of these categories is at relatively low to moderate risk of having high-grade disease or cancer (most studies place the risk of high-grade disease at 8%–20% for ASC-US, 20%–50% for AGC, and 10%–30% for LSIL), the commonness of these Papanicolaou (Pap) test readings results in 70% of all high-grade lesions being detected from referrals from these 3 groups.8 

Furthermore, reassessment of false-negative Pap tests that have preceded detection of cervical cancer often results in reclassification of the cytology as ASCUS.9 These Pap tests most commonly have very few abnormal cells, which are also usually very small and difficult to interpret. False-negative cytology has enormous medicolegal implications, for it has been estimated that cervical cytology accounts for only approximately 2% of the US laboratory workload, but up to 80% of laboratory litigation costs. It is understandable, therefore, that cytopathologists may tend to err on the side of caution, leading to an increase in the proportion of smears classified as atypical.10 

The 1999 evaluation of cervical cytology by the Agency for Health Policy Research used a stringent meta-analysis of the literature in estimating the true sensitivity of the Pap test for any CIN to be approximately 51%,11 and although the sensitivity for high-grade disease alone is likely to be higher, it varies greatly from study to study. In contrast, the sensitivity of HPV testing is consistently high from one study to another, as the test eliminates the subjectivity and variability in experience that affects Pap test statistics. Additionally, unlike the Pap test, which can determine only whether abnormal cells are presently detected, HPV testing has predictive value for lesions that may develop in the future.12–15 For example, Konno and colleagues12 retrospectively tested cervical biopsy samples obtained months or years before the diagnosis of CIN or cervical cancer, demonstrating that most women (16 of 18) had detectable high-risk HPV types for up to 10 years prior to the diagnosis of cancer. Similar results have been obtained on retrospective testing of false-negative Pap tests preceding cervical cancer, all testing positive for the same HPV type as found in the cancer for a median of 12 years before the diagnosis of cancer.15 

The problem of equivocal smears has been highlighted in a number of studies in which Pap tests originally classified as borderline/ASC-US were submitted for repeat assessment to a group of expert cytopathologists. In one study, 5 expert cytopathologists reread 200 Pap tests originally classified as atypical and were not able to unanimously agree on a single smear as being ASCUS.16 In the ASCUS/LSIL Triage Study (ALTS), a National Cancer Institute–sponsored US $28 million evaluation of the options for the management of ASCUS and LSIL, a cytopathology review panel did not agree with the original Pap test interpretation of ASCUS in approximately 50% of cases. Most of the interpretations that were revised were downgraded to normal.17 Since one pathologist's “ASCUS” may be read by another as “normal”, or another may read it as “LSIL,” many Pap tests at the lower end of the abnormal cytologic spectrum may be misclassified.18 The likelihood of misclassification increases with a woman's age, possibly due to the effects of declining estrogen levels on the cervical epithelium and to other aspects of aging.19 Increasing misclassification with increasing age results in fewer older women with equivocal or low-grade Pap test abnormalities being confirmed at colposcopy. For example, in a study in the United Kingdom, Giles and colleagues20 evaluated women having 1 Pap test classified as mild dyskaryosis; 30% of those aged 25 to 35 years were found to have normal cervices at colposcopy compared with approximately 65% of those older than 35 years. Compared to false-negative Pap tests, the cost and anxiety created by these false-positive tests are probably greater. Furthermore, it must be remembered that, particularly in young women, even genuinely positive Pap tests often are due to transient HPV-induced, low-grade lesions and yet create considerable anxiety and unnecessary cost.21 

Because of the nearly universal association of cervical cancer with certain high-risk types of HPV,22 an obvious approach for improving the management of equivocal Pap tests would be to focus on those patients who test positive for the high-risk HPV types. Human papilllomavirus–negative, cytologically normal women are at extremely low risk for CIN 3+ and can be reassured, whereas women positive for high-risk HPV types are at higher risk, justifying referral for colposcopic assessment.3,4 The objectivity of the HPV test serves to clarify the meaning of an equivocal Pap test; in the cited studies in which cytopathologists largely failed to agree on the classification of equivocal smears, the highest agreement was achieved on the Pap tests identified as HPV-positive.16 

Recent studies using Hybrid Capture 2 (Digene Corporation, Gaithersburg, Md) have consistently documented a sensitivity of about 90% to 96% for the presence of high-grade CIN (CIN grades 2 and 3), whereas the average sensitivity for the repeat conventional Pap test in the same studies has been approximately 75%,2,3,23 and in ALTS the sensitivity for improved liquid-based cytology was 85% (ThinPrep Pap, Cytyc Corporation, Boxborough, Mass).4 Additionally, in ALTS at the threshold for referral to colposcopy of ASCUS or higher, slightly more women (59%) were referred to colposcopy on the first repeat Pap test than for HPV testing (56%).4 Repeat Pap testing with a threshold of LSIL or higher would have referred far fewer patients to colposcopy (25%) but would have detected inadequate numbers of women with CIN 3+ (64%). Long-term, 2-year follow-up data confirmed that further repeat cytology at this threshold never attained the same level of detection of CIN 3+ as did immediate HPV testing, and as would be expected, an HSIL or higher threshold was found to be totally inadequate. Both HPV testing and repeat Pap testing referred more women aged 29 years or younger with ASC-US to colposcopy than older women, but HPV testing had significantly higher sensitivity for CIN 2 and 3 and held the advantage at all ages.24 Because testing for HPV was so sensitive, triage on the basis of a combined repeat Pap test and an HPV test did not substantially increase detection of high-grade CIN, but would have significantly increased referral to colposcopy. Also, the reassurance provided by a single negative HPV test prompted the recent ASCCP Guidelines to recommend repeat Pap test for HPV-negative women with ASC-US to be at 12 months.6 

The ALTS findings indicate that a triage strategy of repeat Pap testing would require 2 repeat liquid-based Pap tests to equal the sensitivity of Hybrid Capture 2 for detection of CIN 3+. Therefore, the disadvantages of repeat Pap testing include a significantly higher total cumulative referral to colposcopy (67% following the second repeat Pap test) and delayed detection of CIN 3+ in comparison with immediate detection by HPV testing of almost all women at risk for having CIN 3 or cancer. The repeat Pap test triage arm would also have to be the most expensive, as at least 67% would eventually have colposcopy, with the additional expense of a repeat Pap test and office visit for 100% and a second repeat Pap test and office visit for another 42%.25 

ASCCP Guidelines for the Management of ASC-US

If the cytology that generated the ASC-US Pap test is a conventional Pap test, there is no clearly obvious advantage of one management strategy over another, for both repeat cytology and HPV testing require return of the patient for at least 1 more office visit. Therefore, the ASCCP Guideline for the management of women with ASC-US states that “a program of repeat cervical cytology, or colposcopy, or HPV DNA testing for high-risk types of HPV are all acceptable methods for managing women with ASC-US” (Figure 1).6 In contrast, when liquid-based cytology is used, or when co-collection of HPV DNA testing can be done, “reflex” HPV DNA testing was the preferred approach recommended by the ASCCP conference delegates. Reflex HPV testing as a management option for women with ASC-US derived from a liquid-based Pap test has a distinct advantage because the HPV test can be taken directly from the remaining liquid-based cytology sample, thereby eliminating the need for a woman to return for a repeat office visit. If the cytopathology laboratory has in-house HPV testing available, the Pap test result can be reported as “ASC-US HPV negative” or as “ASC-US HPV positive.” If the HPV test must be done in a separate reference laboratory, then the cytopathology laboratory can be instructed to automatically send all liquid-based samples with ASC-US results to the appropriate reference laboratory, and the Pap test results and HPV results will likely be reported separately. “Co-collected HPV test” refers to the option of collecting an HPV test in a commercial viral transport media on all women having a Pap test, but holding on to the HPV test samples until the Pap test result returns. Only the HPV test samples collected from women with a report of ASC-US would be sent to the laboratory for testing, and all remaining test samples (approximately 95/100) would be discarded as medical waste.

The ASCCP Guidelines recommend that HPV DNA testing should be conducted only for the high-risk panel of HPV types and that the test chosen should be a sensitive molecular test.6 At this time, the only molecular HPV DNA test approved for ASCUS triage is Hybrid Capture 2. As discussed previously, high-risk HPV types are the only types found in cervical cancers and, for the most part, the only types found in true high-grade CIN (grades 2 or 3). Because cervical cytology is a screening test for cervical neoplasia, not a screening test for sexually transmitted diseases, ordering the low-risk panel of HPV types involved only in the causation of genital warts and low-grade transient cervical cell changes (CIN 1) is not helpful and adds to the cost for the patient. All women who are positive for high-risk HPV DNA should be referred for colposcopic evaluation.6 Women with ASC-US who are negative for high-risk HPV DNA can be followed up with repeat cytology at 12 months.6 The reason that this particular interval for follow-up was chosen is that the ALTS data clearly indicated that the sensitivity for detection of high-grade CIN and cancer is so high (96%),4 and therefore the negative predictive value is correspondingly so reassuring, that follow-up in 12 months is appropriate.

If repeat conventional or liquid-based cytology is chosen as the follow-up method for women with ASC-US, the Pap test should be repeated at 4- to 6-month intervals until 2 consecutive “negative for intraepithelial lesion or malignancy” results are obtained.6 Two repeat Pap tests was chosen as the number of repeat Pap tests necessary to equal the sensitivity of 1 HPV test. The basis for this management recommendation is ALTS data showing that it took 2 repeat liquid-based Pap tests to equal the sensitivity of a single HPV test in the triage of women with an initial ASC-US Pap test. The most appropriate Pap test threshold for referring women to colposcopy has been evaluated in several studies and appears to be a repeat cytology result of ASC or greater.2–4 This is because referral thresholds of LSIL and HSIL on the repeat Pap test misses many women with biopsy-confirmed CIN 2/3. After 2 normal repeat Pap tests are obtained, women can be returned to routine screening, as the sensitivity for detection of CIN 2 or 3+ is comparable to the same sensitivity of a single HPV test, which when negative is also recommended to return for routine screening.26 

The third option for monitoring women with ASC-US that is considered acceptable is immediate colposcopy.6 Women found to be negative on colposcopy can be reassured and returned to repeat cytology in 12 months.6 However, in ALTS more than 22% of the CIN 2/3 lesions detected during 2 years of follow-up were not identified at the single initial colposcopy examination.26 Therefore, women with negative findings for high-grade CIN on colposcopy should remain in a follow-up notification program for increased assurance of attendance at 12 months.6 

Management of ASC-US in Special Circumstances

There are several special circumstances in which management of ASC-US may differ somewhat from the general management recommendations just discussed,6 including management of ASC-US in postmenopausal women and in immunosuppressed women. A finding of ASC-US in pregnant women is a special circumstance, but there are no recommended differences in the management of these women. Therefore, they will not be discussed separately here.

All 3 management options—immediate colposcopy, repeat Pap testing, and HPV DNA testing—are considered acceptable options for the management of postmenopausal women with interpretations of ASC-US (Figure 2).6 Human papillomavirus–negative ASC-US is increasingly common in women older than 30 years and is not associated with CIN 2+.24 These HPV-negative epithelial changes are likely to be due to declining estrogen levels and general changes in the epithelium throughout the body that occur with increasing age. In ALTS, only 31% of the women with ASCUS older than 29 years tested positive for HPV, in contrast to 65% to 70% of women with ASCUS younger than 29 years.24 Therefore, for women in the perimenopausal and postmenopausal age group, and for women of any age on Depo-Provera who have clinical or cytologic evidence of atrophy and no contraindications to using intravaginal estrogen, an acceptable management option is to provide a course of intravaginal estrogen followed by repeat cervical cytology obtained approximately 1 week after completing the regimen.6 When this option is taken, the repeat cytology should be done 1 week after completion of therapy, and any woman with a result on repeat Pap testing of ASC-US or greater should be referred for colposcopy. If the repeat cervical cytology is normal, then the cervical cytology should be repeated in 4 to 6 months. If atrophy is likely to continue, repeating the course of vaginal estrogen prior to the appointment for each Pap test may be advantageous. If both repeat cytology tests are normal, the patient can return to routine cytologic screening.

Atypical squamous cells of undetermined significance, HPV detection, and CIN are all 2 to 3 times more common in women infected with human immunodeficiency virus (HIV) than in HIV-negative women.27 Additionally, the majority of ASC-US Pap tests in these women are HPV-positive. Therefore, testing for HPV as a triage for ASC-US is not efficient for women who are immunosuppressed. Additionally, immunosuppressed women having ASC-US are at greater risk of having CIN 2+. These findings all support the recommendation that all immunosuppressed women with ASC-US should be referred to colposcopy. This recommendation includes all HIV-infected women, irrespective of CD4 count, HIV viral load, or antiretroviral therapy.6 The difference in risk for HIV-positive versus HIV-negative women is clearly illustrated by the large multicenter Women's Interagency HIV Study, a prospective cohort study that enrolled 1639 HIV-positive and 452 HIV-negative women.27 All women had HPV testing and cytology, T-cell subsets, and plasma HIV-RNA levels at baseline and every 6 months during the 5-year study period (1994 to 1999). One or more abnormal Pap tests were found in 73% of HIV-positive and 42% of HIV-negative women. Papanicolaou tests designated HSIL occurred in 6% of patients in the HIV-positive group, while being expected in less than 1% of HIV-negative women during the same period. The incidence of having at least 1 or more ASCUS Pap tests was 26 per 100 person years for HIV-positive women in contrast to 11 per 100 person years for HIV-negative women, whereas for LSIL Pap tests it was 8.9 per 100 person years for HIV-positive patients in contrast to 2.2 for HIV-negative women.

As reviewed previously, the management of women with ASC-H differs from that for ASC-US.6 This variance is due to the higher prevalence of CIN 2/3 among women referred to colposcopy for the evaluation of ASC-H compared to women referred for the evaluation of ASC-US.28 In published studies, 24% to 94% of women with ASC-H have biopsy-confirmed CIN 2/3.28,29 This higher risk suggests that these women should be managed differently than women with ASC-US. The recommended management of women with ASC-H obtained using either conventional or liquid-based cervical cytology is referral for colposcopic evaluation (Figure 3).6 If no lesion is identified after colposcopy in women with ASC-H, it is recommended that, when possible, a review of the cytology, colposcopy, and histology be performed. However, it must be remembered that ASC-H is not equivalent to HSIL, in that these are cells that are suspicious but not confirmatory for high-grade disease. Therefore, management of women with ASC-H found to be negative for high-grade disease at colposcopy is not the same as management under similar circumstances of women with HSIL cytology. Instead of management by an excisional procedure, as would most commonly be done for nonconfirmed HSIL cytology, it is recommended that nonconfirmed ASC-H result in review of the cytology, colposcopy, and histology (if any).6 If the review yields a revised interpretation, management should follow guidelines for the revised interpretation. For instance, if the Pap test interpretation is changed to HSIL, then further management would follow that recommended for women with a noncorrelating HSIL Pap test. Because of the potential for overtreating significant numbers of women, diagnostic excisional procedures, such as loop electrosurgical excision procedure, should not be used routinely to treat women with any ASC (ie, ASC-US or ASC-H) in the absence of a biopsy-confirmed CIN. Therefore, if a cytologic interpretation of ASC-H is upheld, either cytologic follow-up at 6 and 12 months or HPV DNA testing at 12 months is acceptable. Women who are found to have ASC-US or greater on the repeat cervical cytology or who are subsequently positive for high-risk HPV DNA should be referred for a repeat colposcopy.6 

A Pap test interpretation of LSIL, particularly in young women, is too accurate of a marker for high-risk HPV for HPV testing to be helpful.5,25 For a secondary triage test to be cost-effective, it must identify enough women not needing an expensive follow-up test (ie, colposcopy) to more than pay for the additional cost of the triage test (HPV test) by savings accrued from decreased referral to the diagnostic procedure.24,25 Alternatively, the test must identify a significant proportion of patients thought to have disease as being misclassified (false-positive, or overcalled, Pap tests). These requirements are fulfilled for the triage of ASC-US by HPV testing. However, for women with LSIL, the savings from avoided colposcopies are outweighed by the costs of testing due to the high rate of high-risk HPV DNA positivity (83%).5 This finding confirms that LSIL cytology in women younger than 30 years is rarely misclassified. The ALTS group concluded that HPV testing of young women with LSIL was not helpful owing to this high rate of HPV detection.5 

These statistics confirm that women with LSIL require additional evaluation, but it should be recognized that invasive cervical carcinoma is rare in this population.6 Approaches that have previously been recommended for managing women with LSIL include performing colposcopy and repeating cervical cytology at specified intervals. Colposcopy allows women with CIN 2/3 or cancer to be rapidly identified and would be expected to reduce the risk that women with significant lesions would be lost to follow-up. Possible advantages of using repeat cytology to manage women with LSIL are that it reduces the requirement for colposcopy and provides an opportunity for transient CIN 1 lesions to spontaneously regress. However, the disadvantages include high loss to follow-up; that an ASC or greater abnormality will be reported on 53% to 76% of women on the first repeat cervical cytology,5 necessitating colposcopy; and that invasive cancers have been identified in most large studies that have followed women with LSIL by repeat cytology. For instance, Robertson et al30 evaluated a cohort of 1781 women with LSIL followed with repeat cytology. By 24 months, 35% of the women had 2 consecutive negative cervical cytology results, 11.5% had biopsy-confirmed CIN 3 or invasive cervical cancer, and 24% of the women were lost to follow-up.30 Repeat cytology with an LSIL or greater threshold is too insensitive to detect all women with CIN 2 or 3, and follow-up at a lower threshold refers too many women to colposcopy. Therefore, the ASCCP Guidelines recommend that women given the Pap test interpretation of LSIL have colposcopic evaluation (Figure 4).6 Once colposcopy has been performed, subsequent management options depend on whether a lesion is identified; whether the colposcopy is satisfactory; or whether the patient is pregnant, adolescent, or postmenopausal.6 

LSIL in Special Circumstances

There are 3 special circumstances in which LSIL recommendations vary from those just discussed: LSIL in postmenopausal women, LSIL in adolescents, and LSIL in pregnancy. Increased misclassification of LSIL noted in women older than 35 years is likely to be responsible for declining detection of CIN at colposcopy for women of this age with LSIL.20 The probability that many of these noncorrelating Pap tests are misclassified is further supported by detection of HPV DNA in only 30% to 50% of women of this age group with LSIL.31,32 This HPV-positive rate is similar to that reported in HPV testing of women with ASCUS, and the sensitivity of Hybrid Capture 2 for CIN 2/3+ is also identical. Because HPV testing may be as helpful in the triage of older women with LSIL as it is for women with ASC-US, an acceptable management option for selected postmenopausal patients with LSIL is follow-up without initial colposcopy using a protocol of either repeat cytology at 6 and 12 months with a referral to colposcopy threshold of ASC, or HPV DNA testing at 12 months (Figure 5).

Repeat cytology is also an acceptable management option for postmenopausal women with LSIL. If the patient has clinical or cytologic evidence of atrophy and no contraindications to estrogen therapy, treating the cervix and vagina with a course of intravaginal estrogen therapy and repeating the cytology 1 week after completion of therapy is acceptable.6 If no signs of atrophy are present, repeat cytology at 6 and 12 months without first treating with vaginal estrogen cream is appropriate. When repeat cytology is chosen as the option for management of postmenopausal women and the repeat Pap test is negative, the Pap test should be repeated again in 4 to 6 months, and if negative, the patient may resume routine screening. This management algorithm is the same whether it be in the follow-up of women treated by intravaginal estrogen therapy followed by repeat cytology a week after completion of the estrogen regimen, or in the follow-up of postmenopausal women with LSIL who are not treated with vaginal estrogen due to lack of evidence of atrophy, and who have their Pap test repeated 6 months after the index Pap test. If either of the repeat Pap tests are identified as ASC or greater, then referral to colposcopy is appropriate. If instead the management option chosen is an HPV DNA test at 12 months after the index Pap test, women found to be HPV positive should have colposcopy, and women who are HPV negative should return for repeat cytology at 12 months. Although the ASCCP algorithm depicts only the repeat cytology and HPV testing options deemed acceptable for some postmenopausal women with LSIL cytology, immediate colposcopy is also an option for these women, as per the primary LSIL management algorithm for all women.

Adolescents are a special circumstance in that they have high rates of LSIL and high rates of HPV DNA infection.33 In most adolescents, both HPV infection and LSIL cytology are transient phenomena, and cervical cancer is virtually nonexistent. Therefore, in selected adolescents deemed to be reliable, follow-up without initial colposcopy using a protocol of either repeat cytology at 6 and 12 months, with referral to colposcopy threshold of ASC or greater, or HPV DNA testing at 12 months is an acceptable option (Figure 6). Although repeat cytology and HPV testing options are deemed acceptable for some adolescents with LSIL cytology, immediate colposcopy is also an option, as per the primary LSIL management algorithm for all women.

In contrast to the management of ASCUS by HPV testing, which has been well evaluated, there is not yet much in the literature about HPV testing in the management of AGC. However, a large study of ASCUS by the group at Kaiser Permanente also produced data on AGUS, although in much smaller numbers due to the relative infrequency of the diagnosis. The data in this study indicated that HPV testing may serve a useful role in the management of AGUS. In the 137 women with AGUS, 100% of adenocarcinoma in situ cases and 92% of CIN 2 and 3 cases were detected by Hybrid Capture 2 in comparison to 67% of the same lesions detected by repeat cytology.34 Overall detection of high-grade squamous lesions and adenocarcinoma in situ combined was 94% with a positive predictive value of 41%, compared to sensitivity of 62% and a positive predictive of 23% for repeat cytology. For women older than 35 years, the new ASCCP Guidelines call for endometrial sampling in addition to colposcopy and endocervical sampling, owing to the increasing likelihood that an AGC Pap test may represent endometrial disease.6 Because endometrial disease would not be secondary to HPV, HPV testing of women in this age group could miss a significant lesion, although most women with endometrial cancer are symptomatic and might not be missed for this reason. Additionally, the very high risk of AGC “favor neoplasia” or of adenocarcinoma in situ would warrant colposcopy regardless of HPV result. One possible option for the use of HPV testing in the management of women with AGC would be for women with negative findings for high-grade disease on colposcopy and endocervical sampling to provide guidance on whether the patient requires increased surveillance or may be further reassured. However, no data exist to provide guidance on what “further reassurance” or “increased surveillance” would mean in terms of further follow-up. Therefore, the ASCCP Consensus Guidelines did not recommend the use of HPV testing in the management of AGC at this point in time.6 

The ASCCP Guidelines related to the management of women either not found to have any CIN at initial colposcopy or found only to have CIN 1 and not treated were based in large part on longitudinal ALTS follow-up data presented at the Consensus Conference and later published in an abstract in the Journal of Lower Genital Tract Disease,26 with eventual publication as 2 of the 4 main ALTS articles in 2003.35,36 Guido and colleagues26 evaluated the various management strategies in ALTS for the follow-up of women who were not found to have high-grade disease at initial colposcopy. The cumulative CIN 2/3+ diagnosed in the group of women referred initially for the evaluation of HPV-positive ASC or LSIL and not found to have high-grade disease at initial colposcopy was 7%. This risk for subsequent detection of CIN 2/3+ confirms that all women referred for these Pap test abnormalities but not found to have CIN 2+ initially continue to be at increased risk for detection of high-grade CIN.

The risk of detection of CIN 2+ was essentially identical for women referred for these Pap test abnormalities and either found to have CIN 1 and managed expectantly or not found to have any CIN on initial referral.35 Therefore, management of all women referred for these Pap test abnormalities but not found to have CIN 2 or 3 on initial colposcopy will be similar irrespective of whether CIN 1 or no disease was found at initial colposcopy. Both management strategies with high sensitivity for the detection of CIN 3+ would have referred greater than 50% back for a second colposcopy. Human papillomavirus testing at 12 months was 95% sensitive for the detection of CIN 3+ with referral of 55% back to colposcopy.36 Repeat cytology at 6 and 12 months cumulatively detected 88% of the CIN 3+ cases, while referring approximately 63% back to colposcopy.

Therefore, the ASCCP Guidelines for women not found to have CIN 2+ at initial colposcopy and referred for either HPV-positive ASC-US or LSIL recommend either HPV testing at 12 months or repeat cytology at 6 and 12 months.6 Women testing HPV positive for high-risk types at 12 months should be referred back to colposcopy, as should women managed by repeat cytology and having ASC-US or greater on either Pap test repeat. Women negative for high-grade CIN on both repeat Pap tests or on the single HPV test are at low-risk of having missed CIN 2+ or cancer and can return to routine screening. Additionally, documentation that women who become HPV negative on follow-up most often return to normal cytology, that there is substantial evidence that only persistent HPV progresses to CIN 3,14 and that testing for high-risk HPV detects most CIN 34,36 has established a single repeat HPV test as the primary alternative to 2 repeat Pap tests in the follow-up of women with CIN 1 histology or less.6,26,36 Human papillomavirus testing is also suitable for follow-up after treatment with cryosurgery, loop electrosurgical excision procedure, laser, or cold knife conization, for which proof of return to an HPV-negative state provides further reassurance of clearance of cervical disease.37,38 

Note.—The Consensus Guidelines algorithms originally appeared in and are reprinted from The Journal of Lower Genital Tract Disease, 2002;6(2), and are reprinted with the permission of the American Society for Colposcopy and Cervical Pathology (ASCCP). Copyright 2002, ASCCP. No copies of the algorithms may be made without the prior consent of ASCCP.

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Presented at the College of American Pathologists Strategic Science Series Conference, HPV Testing: Are You Ready for a New Era in Cervical Cancer Screening?, Rosemont, Ill, September 21–22, 2002.

Author notes

Reprints: J. Thomas Cox, MD, Gynecology Clinic Health Services, University of California, Santa Barbara, El Colegio Rd, Santa Barbara, CA 93106 ([email protected])