CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 2, 292–301 r 2014, Lippincott Williams & Wilkins

Secondary Prevention of Cervical Cancer Part 2: Initial Management of Abnormal Cervical Cancer Screening Test RICHARD GUIDO, MD Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, Pennsylvania Abstract: Cervical cancer screening has become more complex with the addition of HPV testing to pap testing. This chapter covers evidence based national recommendations for managing abnormal cervical cancer screening tests. Key words: cervical cancer, screening, colposcopy, management

evidence or, when not available, the opinion of thought leaders in the field. The guidelines developed from the most recent consensus conference were supported by data from 1.4 million women followed prospectively in the Kaiser-Permanente Northern California Medical Care Plan.5 This data was instrumental in providing age-based risk assessment for the development of CIN-2+ as well as providing relatively long-term follow-up of this population. The present guidelines also reflect management in the era of less frequent screening as adopted nationally following the most recent American Cancer Society (ACS) led consensus conference.6 The most recent consensus conference used the fundamental principle that patients with equal risk level for the development of CIN-2+ should be managed in a similar manner and once again adopted a number of terms to describe recommendations. These recommendations are summarized in Table 1.4 These

Evidence-based guidelines for the management of abnormal pap and human papilloma virus test have been the cornerstone for management for the last decade. The American Society of Colposcopy and Cervical Pathology (ASCCP) consensus conferences that occurred in 2001, 2006, and 20121–4 were specifically designed to incorporate the key organizations involved in cervical cancer screening in the United States and provide recommendations based on the best Correspondence: Richard Guido, MD, Magee-Womens Hospital of the UPMC System, University of Pittsburgh, Pittsburgh, PA. E-mail: [email protected] Richard Guido is a board member for ASCCP. CLINICAL OBSTETRICS AND GYNECOLOGY

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Management of Abnormal Cervical Cancer Screening Test TABLE 1.

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Rating the Recommendations

Strength of Recommendation A Good evidence for efficacy and substantial clinical benefit support recommendation for use B Moderate evidence for efficacy or only limited clinical benefit supports recommendation for use C Evidence for efficacy is insufficient to support a recommendation for or against use, but recommendations may be made on other grounds D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use Quality of evidence I Evidence from at least one randomized, controlled trial II Evidence from at least one clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies, or dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. Terminology used for recommendations Recommended Good data to support use when only one option is available Preferred Option is the best (or one of the best) when there are multiple options Acceptable One of the multiple options when there is either data indicating that another approach is superior or when there are no data to favor any single option Not recommended Weak evidence against use and marginal risk for adverse consequences Unacceptable Good evidence against use Modified from Gross et al.19 and Kish.20 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. The assignment of these terms represents an opinion ratified by vote during the 2012 consensus conference.

recommendations are easy to interpret, have become established, and help clinicians in understanding the strength of a particular recommendation. The management guidelines presented here use the Bethesda system of cytologic terminology.7 This standard is well established, and although it has some limitation in terms of reproducibility, it has been standardized throughout the United States. HPV testing has evolved considerably since its introduction in the 90s; however, it is well established that only high-risk HPV is the cause of cervical cancer and, therefore, when positive an HPV test refers to a test indicated that it is positive for one of the established high-risk HPV types. In 2012 a consensus conference was arranged to harmonize the histologic terminology for the lower genital tract squamous epithelium in both men and women. This

conference, The Lower Anogenital Squamous Terminology Project, was organized by the College of American Pathologist and ASCCP focused on eliminating some of the confusion in terminology, especially in the area of cervical histology.8 The terminology specifically divides cervical disease into lowgrade intraepithelial and high-grade intraepithelial disease. The division is biologically based and uses immunologic staining for P16 to differentiate the prior diagnosis of CIN-2 into either high or low risk. The terminology was not specifically incorporated into the ASCCP 2012 consensus conference recommendation, as it has not been thoroughly validated in clinical practice. The recommendations provided in this chapter incorporate the CIN terminology. Management of cytologic abnormalities varies considerably based on the age of the patient. The present recommendations are www.clinicalobgyn.com

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broadly divided into women aged 21 to 24, 25 to 29, 30 years and older, and older than 65 years. In women aged 21 to 25 years, HPV is prevalent, cervical cancer is rare, and therefore there is limited value to HPV testing. The 2012 consensus conference reflects a better understanding of HPV disease in this age group. Women above 30 years of age now have HPV co-testing performed for routine screening. This group represents a group of particular interest, as persistent HPV disease in this population is considered a strong risk factor for developing CIN-3. With the advent of HPV typing, and a better understanding of risk stratification by HPV type, the new guidelines incorporate HPV typing when clinically helpful. Type 16 and type 18, which make up 70% of all cancers, have been identified as the most concerning HPV types and, as such, require the closest evaluation.

Unsatisfactory Cytology Unsatisfactory cytology is an infrequent cytologic diagnosis, especially in the era of the liquid-based cytology. Although in the past obscuring blood or inflammation was a common cause for an unsatisfactory cytology, the most common cause today is a lack of squamous epithelium.9 As some HPV test do not account for cellularity, the consensus conference recommendation for unsatisfactory cytology is to repeat the pap test in 2 to 4 months for women with an unknown or negative HPV test. Women who are above 30 years of age and have cotesting that is positive for HPV can either undergo a colposcopy immediately or have a repeat co-test in 2 to 4 months. If the follow-up Pap test is still unsatisfactory the patient should undergo a colposcopy. If the repeat test pap is negative and was preceded by a negative or unknown HPV test, the patient can return to routine screening. If they had a positive HPV test and a negative screen at the 2- to 4-month repeat test, they should be co-tested at 12 months. www.clinicalobgyn.com

Cytology That is Reported as Negative, but With Insufficient or Absent Endocervical (EC) or Transformation Zone (TZ) Prior recommendations for the management of women where there was insufficient or absent EC component often included frequent evaluation, based on the assumption that the lack of the EC/ TZ cell indicated that there was insufficient testing and a potential for missing disease. This assumption has not been validated, and recent analysis suggests that negative cytology in the absence of EC/TZ cells maintains its specificity.10 Women aged 21 to 29 years with a negative cytology and absent or insufficient EC/TZ should undergo routine screening for follow-up, which implies a repeat pap test in 3 years. HPV testing should not be used for triage in this young age group. Women who are >30 years old, where HPV testing is not available, can be managed either by HPV testing (preferred) or by repeat co-testing in 3 years. If the HPV test is negative the patient can return to routine screening. If the test is positive she should return cotesting in 1 year or genotyping.

Negative Cytology and Positive HPV Test The advent of combined pap and HPV testing as the preferred screening method for women 30 to 65 years of age identifies a small number of women with a normal pap test and a positive HPV test. Numerous studies have demonstrated that a woman who is positive for HPV despite having a negative cytology is at increased risk for CIN-3.11 The present ASCCP recommendation for management of women who have a positive HPV test and a negative cytology is based on the natural history of HPV infections. Treatment options include a repeat pap and HPV test in 1 year or HPV

Management of Abnormal Cervical Cancer Screening Test genotyping to determine if the patient is positive for type 16 or 18. Those individuals who have either a persistent positive HPV test or any cytologic abnormality at one year will require a colposcopy. Those triaged to a genotype test who test positive for type 16 or type 18 will require immediate colposcopy.

ASC-US The Bethesda system introduced the term atypical squamous cells of undetermined significance. This is one of the most common cytologic abnormalities that occur in women undergoing pap smear screening. It represents a fairly heterogenous group of women with a variable rate of human papilloma virus positivity. In the ALTS trial HPV positivity ranged from 35% to 50%.12 The original ALTS trial did not include the diagnosis of atypical squamous cells cannot rule out high-grade. The latter group has been determined to be at significantly increased risk of CIN-3. The ALTS trial has demonstrated that triage of women who are HPV-positive to immediate colposcopy detects a high percentage of women who ultimately are identified as having CIN-3, while referring a lower number of women to colposcopy. The preferred technique for managing women with atypical squamous cells of undetermined significance is colposcopy for women who test positive for HPV. Because of the variation and health care delivery system across the United States, repeat cytology is considered acceptable methods of management. Figure 1 summarizes the most recent consensus conference recommendation for the management of atypical squamous cells of undetermined significance. The most recent changes in the ASCCP management guidelines reflect a new understanding of the long-term risk of developing CIN-3 based upon an individual’s presenting cytology. Katki et al5 have published follow up data on women

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based on their intial cytology. Women with ASC-US HPV-positive who have CIN-1 or less at the initial colposcopy are at a 10% risk of developing CIN-2 to CIN-3 during the next 5 years of follow-up. On the basis of this relative low risk of developing CIN-2 to CIN-3, after initial colposcopy follow-up of this patient population includes cytology and HPV testing only once in 12 months.

Low-grade Squamous Intraepithelial Lesion (LSIL) The cytologic diagnosis of LSIL is the second most common diagnosis in Pap smear screening. Women who have a diagnosis of LSIL have a similar risk of developing CIN-2+ as women who are ASC-US HPV-positive. The ALTS trial demonstrated the high percentage of women, >80%, who have a diagnosis of LSIL are positive for high-risk HPV types.13 There is very little benefit of performing HPV testing in the population of patients and, therefore, there is no reflex testing for HPV for women that have LSIL. Women above 30 years of age who undergo co-testing will have both, HPV results as well as a cytologic diagnosis of LSIL. For those women that are HPV-negative but have the diagnosis of LSIL management options include both colposcopy as well as retesting in 1 year. This is based on their relatively low risk of developing CIN-2+ (5%).5 Women who have LSIL and are HPV-positive or those who have LSIL alone require immediate colposcopy. Figure 2 summarizes the present recommendation for the management of women aged 25 years or older who have an LSIL diagnosis. In general, all individuals being evaluated for cytologic abnormalities require adequate colposcopy of the entire cervix and upper vagina for full interpretation and cervical biopsies when lesions are www.clinicalobgyn.com

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FIGURE 1. Management of women with atypical squamous cells of undetermined significance (ASC-US) on cytology. rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

identified. The present recommendations require EC sampling for those individuals where the squamocolumnar junction is not fully visualized or if the patient has no lesions and is not pregnant.

HPV testing at 12 and 24 months. The rationale for the 2 year follow-up is based on the higher risk of harboring CIN-2+ . Management for women aged below 25 years will be discussed below.

ASC-H

High-grade Squamous Intraepithelial Lesion (HSIL)

Atypical squamous cell (ASC) cannot rule out high-grade is a relatively rare cytologic diagnosis that represented at-risk population for developing CIN-2+ . This population of patients has HPV positivity rate that is similar to LSIL and has been found in numerous studies to have a risk of CIN-2+ of approximately 40%.14 Therefore, women of all ages with an ASC-H warrant immediate colposcopy. Given the high rate of CIN-2+ in this population, follow-up for a colposcopy, that is, CIN-1 or less includes pap and www.clinicalobgyn.com

The diagnosis of HSIL is of concern in all women. Because of the fact that approximately 60% of all individuals with this diagnosis have CIN-2 or greater, management guidelines included immediate seeand-treat therapy and colposcopy for women aged 25 years and above. Immediate excisional therapy is implied with the terminology ‘‘see-and-treat.’’ This therapy provides a histologic specimen for analysis and is also used to rule out invasive disease. It eliminates the expense

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FIGURE 2. Management of women with low-grade squamous intraepithelial lesions (LSIL). rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

of recurrent visits as well as the cost for evaluation of the initial biopsies and colposcopy. Women under the age of 25 years will be managed differently as outlined below.

ASC-US and LSIL for Women Aged 21 to 24 Years The rate of cervical cancer in the population of women under the age of 25 years approaches 0. In the Kaiser-Permanente study there were no cases of cervical cancer is women aged below 25 years with the diagnosis of LSIL or ASC-US.5 The young women who comprise this age group have a prevalence of HPV of approximately 80% after the initiation of sexual activity, and 90% of those with

an intact immune system will resolve the infection spontaneously with 2 years.15 This is also an age where both men and women are more likely to have multiple partners, resulting in frequent exposure to new HPV types. It is, therefore, of little value to intervene with an invasive test such as colposcopy in the population individuals with virtually no risk of developing cervical cancer. The present ASCCP recommendations for managing women below 25 years of age with LSIL or ASC-US pap test is to observe with cytologic follow-up. Women are referred to colposcopy if they developed HSIL, ASC-H, or AGC or if they have persistent low-grade cytologic abnormalities over 3year period of time. Figure 3 summarizes the management of women aged 21 to 24 with ASC-US and LSIL. www.clinicalobgyn.com

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FIGURE 3. Management of women aged 21 to 24 years with either atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

HSIL and ASC-H in Women Aged 21 to 24 Years HSIL and ASC-H diagnoses in this population of patients require a colposcopic evaluation. Young women are unique in that they have a relatively high rate of resolution of even biopsy-proven CIN-2, CIN-3. Moscicki16 has demonstrated a resolution rate of 68% of CIN-2 lesions in 2 years and a progression rate of 15% in a population of women aged 13 to 24 years. This population does not warrant see-and-treat for the management of a HSIL pap test. The management of the patient who do not have CIN-2, CIN- 3 on biopsy is to undergo a repeat colposcopic examination and pap test every 6 months for 2 years. HPV testing is not included in the evaluation because of the high prevalence of HPV infection in this population. The clinician should obtain www.clinicalobgyn.com

biopsy at the time of a follow-up examination if there is evidence of high-grade disease, or if the pap is still HSIL at 1 year. Excisional treatment is warranted in the case of a persistent HSIL pap test with a biopsy-proven cause at 2 years. Figure 4 summarizes the ASCCP recommendation for this population.

AGC and AIS Atypical glandular cells and AIS represent a relatively rare cytologic diagnosis but one that warrants close evaluation. The data from the Kaiser-Permanente demonstrates that the risk of cancer for this population is similar to that of ASC-H.17 AGC cells can have a variety of origins. Glandular cells from the endocervix, endometrium, fallopian tube, and ovary can present as AGC. The most common histologic diagnosis that is

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FIGURE 4. Management of women aged 21 to 24 years with atypical squamous cells, cannot rule out high-grade SIL (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

identified in the evaluation of an AGC pap is actually a squamous abnormality. AGC pap test are difficult to interpret based on the small size of the cells, and the fact that they tend to cluster even with liquid-based cytology. The cytologist may indicate that the cells are of EC or endometrial origin; however, it is common for this determination to be difficult. AGC can be sub-divided into NOS (not otherwise specified) and suspicious for cancer. The initial evaluation of an AGC-NOS pap is colposcopy and EC sampling. Those patients with an AGC pap wherein the endometrium is specifically identified as the cell of origin can undergo an endometrial and EC sampling before a colposcopic biopsy is obtained, or the colposcopy can be conducted at the initial evaluation. HPV testing should not be used as a triage tool for this cytologic diagnosis. Endometrial

sampling is required for women above 35 years of age, or in women who are at increased risk for endometrial cancer such as obesity, anovulation, and abnormal uterine bleeding. Women who have a diagnosis of CIN2+ or AIS will require therapy as per the ASCCP guidelines for the specific histologic diagnosis. On the basis of the premise that equal risk of developing high-grade disease warrants equal surveillance, women who do not have CIN-2+ or AIS are to be followed with cytology and HPV testing at 12 and 24 months. A woman who has normal pap and HPV at both follow-up visit may return to testing in 3 years. If any abnormality (cytology or HPV testing) is identified, the patient will again require colposcopy. The follow-up algorithm for women with AGC following initial colposcopy is summarized in Figure 5. www.clinicalobgyn.com

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FIGURE 5. Subsequent management of women with atypical glandular cells (AGC). rCopyright, 2013, American Society for Cloposcopy and Cervical Pathology. All rights reserved. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

Pregnant Women Pregnant women represent a group that are managed very conservatively to protect the ongoing pregnancy. The natural history of cervical cancer is one that requires over a decade to proceed from HPV infection to squamous cell cancer.18 The management strategies for pregnant women reflect the slow progression rate of disease. A patient who is aged between 21 and 24 years with an LSIL pap or ASC-US pap should be managed with a postpartum pap. The ASSCP-preferred recommendation for women 25 years and above for any abnormality is to perform colposcopy during pregnancy. During colposcopy EC sampling is unacceptable. Instrumentation of the cervix can lead to a miscarriage or disruption of the amniotic cavity. Cervical biopsy can and should be performed if there is suspicion of cancer or high-grade lesions. Biopsies during pregnancy can produce modest amount of bleeding and the www.clinicalobgyn.com

health care provider should be prepared when such biopsies are performed. It was common place in the past to perform frequent colposcopies during pregnancy. This practice is not considered appropriate for most patients. If a colposcopy is performed and either biopsies or clinical impression is

Secondary prevention of cervical cancer part 2: initial management of abnormal cervical cancer screening test.

Cervical cancer screening has become more complex with the addition of HPV testing to pap testing. This chapter covers evidence based national recomme...
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