revised in2009

Introduction

Guideline for Screening for

Cervical Cancer

These revised cervical cancer screening guidelines for Alberta were developed by a multidisciplinary expert group. They are based on up-to-date evidence regarding existing and new technologies, and on epidemiologic data from Alberta and elsewhere. The revised guidelines recommend major changes in cervical cancer screening initiation and interval, as well as use of laboratory tests. While annual screening is no longer recommended for all women, screening for other health conditions may necessitate more frequent health care encounters. More than 45 types of human papillomavirus (HPV) are transmitted by intimate sexual contact,1 and persistent infection with a carcinogenic type is necessary for cervical cancer to develop.2 HPV is transmitted so easily that the lifetime cumulative prevalence of high-risk infection approaches 80%.3 Most of these infections resolve without symptoms and without treatment. A womans immune system generally clears the virus, in which case any cervical cell changes the HPV infection may have caused resolve on their own.4 When the virus is not cleared, persistent carcinogenic HPV infection may cause precancerous tissue changes that can, over many years, progress to invasive cervical cancer.5 Early detection and treatment during this lengthy precancerous stage can prevent the vast majority of cervical cancer.

Issues

Failure to be screened and being underscreened continue to be major risk factors for cervical cancer in Alberta. Overscreening is resulting in excess investigations and inefficient use of resources and potential harm to women. The impact of newer technologies such as liquid-based cytology, HPV testing, and the HPV vaccine is evolving.

Goal

To assist health care providers and women in optimizing cervical cancer screening in Alberta to decrease invasive cancer and deaths from this preventable disease, while minimizing screening risks.

Summary Recommendations

Recruitment

Widespread Pap testing in Alberta during the past 40 years has resulted in a substantial reduction in cervical cancer mortality. Yet currently, about 30% of Alberta women have not been screened during the preceding three years. Women who have never been screened or are screened irregularly are most at risk for cervical cancer. Improving cervical screening coverage will reduce mortality further, regardless of the technology used.

The above recommendations are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. They should be used as an adjunct to sound clinical decision making.

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Continuity in the relationship between a woman and her care provider has been shown to increase the uptake of cervical cancer screening.6 A prompt by a womans physician or other health care provider advising her to engage in cervical cancer screening is one of the most effective recruitment strategies. Evidence supports both contacting patients when they are due for screening and flagging charts of women who are overdue so they will be identified quickly upon presentation for another problem.7 These approaches are most successful when used in combination. Invitation and recall letters generated and sent by an organized screening program are also effective.8 The Alberta Cervical Cancer Screening Program (ACCSP ) provides this service in some geographic areas. The program will expand throughout the province in the near future. To determine whether the ACCSP sends invitations and screening reminders to women in your area see screeningforlife.ca.

Screening Test
All laboratories in Alberta are converting to liquid-based cytology. Liquid-based cytology facilitates reflex HPV testing in certain circumstances, which can minimize repeat testing and womens apprehension concerning Pap test results. PRacTice PoinT Regardless of the Pap test findings, a woman with a visibly abnormal cervix or abnormal bleeding should be referred appropriately.

Screening initiation
Cervical cancer screening should begin at age 21 or approximately three years after first intimate sexual activity, whichever occurs later. (Intimate sexual activity includes intercourse as well as digital or oral sexual activity involving the genital area with a partner of either gender.)

Screening interval
Within five years, screen with three negative Pap tests at least 12 months apart and then extend the screening interval to every three years. More frequent interactions with health care providers may be necessary for periodic health exams and screening for sexually transmitted infections (STI). These visits do not necessitate cervical cancer screening unless the woman is due. For women older than 69 who have never been screened, screen with three annual Pap tests. If results are negative and satisfactory, discontinue screening.

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incReaSeD SURVeiLLance Some women, because of increased risk or past cervical disease, require more vigilant surveillance. Continue to screen annually: Women who have ever had biopsy confirmed high-grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS), or invasive cervical cancer. Women with these conditions who undergo hysterectomy should have vault smears annually thereafter. Women with immunosuppression who have ever been sexually active. This includes women with human immunodeficiency virus (HIV/AIDS), lymphoproliferative disorders, organ transplantation, and women taking long-term corticosteroids. (See Risk Factor section for more information.)

Discontinuing Screening
Screening may be discontinued for: Women who have had a hysterectomy with the cervix removed for BENIGN DISEASE, as long as there is adequate pathological documentation that the cervix has been removed completely Women older than 69 years who have had at least three consecutive satisfactory and negative Pap tests at the recommended screening interval in the last 10 years

Follow-up and Management of abnormal Pap Tests (see Table 1) Special circumstances
Women under 21 years of age with abnormal results: - Routine screening in this age group is not recommended. Dysplastic lesions in this age group are most likely to resolve spontaneously. If women younger than 21 years are screened, referrals for colposcopy should be minimized while carefully monitoring for progression. See Table 1 for modified follow-up guidelines for women younger than 21 years with Pap test findings of ASC-US or LSIL. - In women younger than 21 years with either ASC-US or LSIL, HPV DNA testing is unacceptable and if inadvertently performed, should not influence management. Pregnant women should be screened according to the guidelines, however care should be taken not to overscreen. There is no need to perform Pap tests during pre-natal and post-partum visits unless the woman is otherwise due for screening. - If ASC-US or LSIL is detected during pregnancy, do not repeat the Pap test until 6 months post-partum. All other findings, especially more advanced lesions, should be managed according to the guidelines.

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Women currently being assessed by a colposcopy clinic, including those who do not show up for their appointments, should not undergo additional Pap testing until discharged from colposcopy. Women who have undergone subtotal hysterectomy and retained their cervix should continue with screening according to the guidelines. Women who have received the HPV vaccine should continue with screening. The HPV vaccine is approved in Canada for females 9 to 26 years of age. It should be recommended to unimmunized women according to NACI guidelines that currently recommend the following:9 - The HPV vaccine should be offered to females before they become sexually active to ensure maximum benefit. The primary age group recommended is 9 to 13 years. - Females 14 to 26 should also be offered the vaccine. Women may potentially benefit regardless of prior sexual activity, Pap test abnormalities, or a known HPV infection. - HPV vaccine is NOT recommended for pregnant women, females under nine years, or males. - For women older than 26 years, consider its use on a case by case basis.

optimal Specimen collection

Advise the patient to avoid, where possible, the use of contraceptive creams and jellies, douching, intravaginal medication, and sexual intercourse for 24 hours before the test.10 Advise the patient to avoid scheduling her appointment during menses, but do not defer for abnormal bleeding. Follow collection instructions provided by the manufacturer. Pap testing should be done BEFORE other cervical procedures including STI testing, IUD insertion, etc., so that the diagnostic cells needed for the Pap test are not removed. Pap tests should not be repeated within 3 months of prior Pap tests or other cervical procedures to allow time for epithelial regeneration. The presence of endocervical cells is not necessary for the sample to be satisfactory for evaluation as per Bethesda 2001. An adequate number of squamous epithelial cells is required.

Advice to Patients

Asymptomatic patients should be aware of the consequences of their decisions to be screened or not screened. The following public education brochures are available from the Alberta Cervical Cancer Screening Program in this regard: cervical Screening: Do i Really need a Pap Test? cervical Screening: Making Sense of abnormal Pap Test Results cervical Screening: Human Papillomavirus (HPV) - What You need to Know and Do

Please see screeningforlife.ca for the cancer screening resource order form or call 1-866-727-3926 (toll free).

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Table 1: Management of abnormal cytology
Pap Test Result Unsatisfactory
atypical squamous cells of undetermined significance (aSc-US)

Recommended Management Repeat Pap test in 3 months

Women < 21 years (Although routine cervical screening is NOT recommended) Repeat Pap test every 12 months for 2 years (2 tests): At 12 months: ONLY high-grade lesions should be referred for colposcopy At 24 months: Negative return to routine screening ASC-US or greater refer for colposcopy Women 21 - 29 years anD women 30 when HPV testing is noT available Repeat Pap test every 6 months for 1 year (2 tests): (tests must be at least 6 months apart) If all negative return to routine screening If either repeat result is ASC-US or greater refer for colposcopy Women 30 years when HPV testing is available* If HPV negative return to routine screening If HPV positive refer for colposcopy

Low-grade squamous intraepithelial lesion (LSiL)

Women < 21 years (Although routine cervical screening is NOT recommended) Repeat Pap test every 12 months for 2 years (2 tests): At 12 months: ONLY high-grade lesions should be referred for colposcopy At 24 months: Negative return to routine screening ASC-US or greater refer for colposcopy Women 21 - 49 anD women 50 when HPV testing is noT available Repeat Pap test every 6 months for 1 year (2 tests): (tests must be at least 6 months apart) If all negative return to routine screening If either repeat result is ASC-US or greater refer for colposcopy Women 50 when HPV testing is available* If HPV negative return to routine screening If HPV positive refer for colposcopy

Atypical squamous cells - cannot exclude HSIL (ASC-H) High-grade squamous intraepithelial lesion (HSIL) Atypical glandular cells (AGC), Adenocarcinoma in situ (AIS)

Refer for colposcopy Refer for colposcopy Refer for colposcopy

Squamous carcinoma, adenocarcinoma, other malignancy

Refer to specialist care

Endometrial cells after the age of 40 should be managed or referred as appropriate

* Where available, the lab will automatically perform HPV DNA testing for women 30 with ASC-US results and women 50 with LSIL

Cervical Cancer
Background

introduction
Cancer of the cervix is the 13th most frequently diagnosed cancer among Canadian women. An estimated 1,300 Canadian women will develop cervical cancer in 2009 and 380 women will die from it.11 The lifetime probability of a woman in Canada developing cervical cancer is now about 1 in 150,11 whereas in the absence of screening, the lifetime probability is estimated to be 1 in 28.12 Between 1969 and 2004 there was an overall reduction in age-standardized mortality from invasive cervical cancer in Canada from 7.4 to 2.0 per 100,000 women and a reduction in incidence during this time from 21.6 to 7.5 per 100,000 women. This decline is mostly attributable to screening. Well over 1,000 lives are saved each year because of cervical screening efforts in Canada and many thousands of cases of invasive cancer are prevented.13 Although the effectiveness of regular screening for cervical cancer is undisputed, a substantial proportion of Alberta women remain underscreened. About 30% of eligible women have not been screened at least once in the past three years. Approximately 150 women are diagnosed with cervical cancer each year in Alberta and roughly 40 women die from this mostly preventable cancer.14 Most of these women are unscreened or underscreened.15

natural History
Squamous cell carcinoma accounts for 80-90% of cervical malignancies and the remainder are mainly adenocarcinoma. Persistent infection with one of the carcinogenic types of HPV is a necessary but not sufficient cause of both squamous and glandular malignancy.2 Both types arise from a four-step progression as follows:5 HPV transmission HPV persistence Development of precancer in persistently infected cells Invasive cervical cancer Close to 90% of carcinogenic HPV infections are cleared spontaneously through cell mediated immunity within two years of infection. Backward progression from persistent HPV infection and from precancer is also possible. Premalignant squamous lesions are classified as either low-grade squamous intraepithelial lesion (LSIL) or high-grade SIL (HSIL). The majority of LSIL appears to clear spontaneously and infrequently progresses to invasive carcinoma.16 In contrast, approximately 13% of untreated HSIL will progress over time to invasive carcinoma. Precancer typically takes 5 to 10 years to develop from the initial HPV transmission.5 In a minority of women with precancer, invasive cancer will develop over many years.5 By detecting women with precancer during this lengthy progression, treatment can be targeted and invasive carcinoma prevented.

Risk Factors
The key determinants of HPV infection among women are the number of sexual partners, the age at which sexual intercourse was initiated and the likelihood that her partner(s) were infected with HPV as measured by their sexual behaviour.17

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Women whose partners use condoms consistently are at lower risk of acquiring HPV infection.18 However, compared with STIs transmitted through genital secretions, condoms provide less protection against infections like HPV that are transmitted through contact with infected skin or mucosal surfaces. These areas are not always covered or protected by a condom. Women who are immunosuppressed have a higher risk of HPV infection and HPV is more likely to persist. For instance, women who are HIV positive are up to 10 times more likely than at-risk HIV negative controls to be infected with HPV, with the risk increasing with declining CD4 counts.19 Even after controlling for the presence and persistence of HPV infection, women with HIV are also 4.5 times more likely to develop precancerous cervical lesions, with the risk increasing with increasing HIV-related immunodeficiency.20 Furthermore, from five years before the date of AIDS onset to five years after this date, women with HIV/AIDS are at least four times more likely to develop invasive cervical cancer compared with the general population of women.21 Women with other conditions associated with immunosuppression are also at increased risk of high-grade precancerous lesions. These conditions include systemic lupus erythematosus,22 inflammatory bowel disease,23 and transplantation.24 Diethylstilbestrol (DES) was given to some pregnant women between 1940 and 1971 to prevent miscarriage. Women whose mothers took DES when pregnant with them have a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. Among women with persistent HPV infection: The most important risk factor for cervical cancer is inadequate cervical screening. Smoking independently increases the risk of cervical cancer by at least two-fold as does high parity.17

initiating cervical cancer Screening

The TOP guideline previously recommended that screening begin at 18 years for women who had ever had sexual intercourse. Cervical cancer is rare in Alberta among females younger than 21 years (see Figure 1). Over the 20 year period between 1988 and 2007, only six cases occurred in this age group (0.6 per 100,000).14 This low rate is expected given the conditions slow malignant progression. High screening coverage in Alberta likely does not account for this low rate a comparably low rate is observed in this age group in Europe, where most countries do not target women for screening before age 25.3 Invasive cervical cancer is rare among younger women because progression from HPV infection to precancer typically takes 5 to 10 years, and development of invasive cancer takes years longer.5 Approximately 50% of women will acquire an HPV infection within four years of sexual debut.25 Screening females who have become sexually active only recently tends to detect transient manifestations of recently acquired HPV infection that are likely to regress spontaneously. Among 13 to 22 year old women with LSIL, 93% will regress spontaneously while only 3% will progress to HSIL within three years.26 Among women younger than age 25 with histologically confirmed CIN 2 or 3, more than half of the lesions will regress without treatment by age 25, while the estimated rate of progression to invasive cancer from CIN 3 is roughly 0.3% per year in this age group.27 Delaying routine screening invitations to age 21 is unlikely to miss invasive

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disease resulting from dysplasia arising in the teenage years. In fact, a recent case-control study in the United Kingdom suggests that screening women aged 20 to 24 has little or no impact on the incidence of cervical cancer.28

Figure 1: Age-specific incidence rates for cervical cancer in Alberta, 1988-2007

The adverse effects of screening include anxiety pertaining to abnormal test results, psychosexual morbidity associated with colposcopy, and risks associated with treatment including consequent obstetric impact (i.e., risk of premature delivery).29,30 With age, the proportion of abnormal Pap test results decreases, but abnormalities among older women are much more likely to be related to progressive disease. The revised guidelines are intended to minimize the potential harm of overscreening, particularly among younger females who benefit the least from Pap testing. While the burden of cervical cancer in this age group is low, the burden of abnormal Pap tests is disproportionately high. Among 18 to 20 year old women screened through the Alberta Cervical Cancer Screening Program, approximately 15% receive at least one abnormal result. And while only 0.2% of cervical cancer cases occur among females younger than 21 years, 10% of all colposcopy referrals are among females in this age group (see Table 2). Delaying screening until women are 21 years of age and have been sexually active for approximately three years will allow most of these lesions to regress, with almost all of the rare few destined to progress still being screen-detectable at a pre-invasive stage.

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Table 2: colposcopy Referrals by age Group in the alberta cervical cancer Screening Program (accSP) 2006-2008
aGe GRoUP (YeaRS) 18-20 21-29 30-39 40-49 50-59 60-69 70 Total nUMBeR ScReeneD* 12,732 68,801 85,156 82,356 61,657 29,409 6,758 346,869
(3.7%) (19.8%) (24.6%) (23.7%) (17.8%) (8.5%) (1.9%) (100%)

nUMBeR ReFeRReD FoR coLPoScoPY ** (9.8%) 1276 (44.3%) 5,745 (23.0%) 2,986 (14.3%) 1,848 (6.0%) 774 (2.0%) 254 (0.6%) 80 (100%) 12,963

% ReFeRReD FoR coLPoScoPY 10.0% 8.4% 3.5% 2.2% 1.3% 0.9% 1.2% 3.7%

* Number of women who had at least one Pap test within the 3 year period ** Number of women referred for colposcopy at least once within the 3 year period Best practice to reduce invasive cervical cancer incidence in Alberta is to develop and implement innovative measures to recruit underscreened women in higher risk groups. Although not recommended on a routine basis, if women under the age of 21 years are screened, their follow-up should be tailored to the high probability that dysplastic changes will resolve spontaneously. A modified follow-up guideline is included for women younger than 21 years (see Table 1). Women under the age of 21 years may still require frequent interaction with health care providers for STI screening, HPV education, and HPV vaccination.

Screening interval
The previous TOP guidelines recommended annual screening. Evidence from observational studies and epidemiologic modeling shows that annual screening offers only minimal additional protection against cervical cancer compared with triennial screening.31,32 This is particularly true after women have had 3 consecutive negative Pap tests.32 These negligible additional gains come at huge costs in terms of multitudes of women being subjected to extra Pap tests and colposcopy, even though most low-grade lesions and many high-grade lesions regress spontaneously. Extension of the screening interval away from annual and towards 3-yearly screening is ideally undertaken in the context of an organized recall program with built-in quality assurance. The Alberta Cervical Cancer Screening Program (ACCSP) provides recall functions to women in some parts of southern Alberta and will roll-out province-wide in the near future. Women all across the province benefit from the programs quality assurance processes for cytology and colposcopy.

Cervical Cancer
increased Surveillance
While extension of the screening interval is safe for many women with negative screening histories, some women should continue to screen annually. This includes women who are immunosuppressed because these women have of an increased likelihood of HPV infection, precancerous lesions, and invasive cervical cancer as described under the Risk Factors section above. Another group that should undergo annual screening indefinitely includes women who have ever had biopsy confirmed high-grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS), or invasive cervical cancer. Despite undergoing treatment, these women have more than twice the risk of invasive cervical cancer compared with the general female population for 25 years or more.33,34 If they have undergone hysterectomy, these women should have vault smears every year.35

Discontinuing Screening
High grade abnormalities and cervical cancer is exceedingly rare among older women with adequate screening histories.32 Cervical cancer among older women occurs almost entirely among those who are unscreened or underscreened. Screening these women can reduce morbidity and mortality. Obtaining satisfactory samples from older women can be challenging because of conditions such as atrophy and cervical stenosis (see Appendix 1). Although the exact age to discontinue screening is somewhat arbitrary, after the age of 69 the potential harms of ongoing Pap testing in well-screened women who are not otherwise at high risk may well outweigh the benefits. Since cervical cancer is so unlikely in these women, the potential benefits are minimal. Women with an intact cervix can generally cease screening after age 69 if they have had at least three consecutive satisfactory and negative Pap tests at the recommended screening interval in the last 10 years. (Women who are immunocompromised and those who have a history of cervical cancer or high-grade cervical abnormalities should continue with annual screening.)

notes on Reporting Terminology: The Bethesda System

The Bethesda (2001) system for reporting Pap tests is the recommended standard for use in Canada and by the Alberta Cervical Cancer Screening Program.36 Reports include a statement of adequacy and the diagnosis. There are two categories of specimen adequacy, Satisfactory for Evaluation and Unsatisfactory for Evaluation. Unsatisfactory for evaluation indicates the test was rejected/not processed or that the specimen was processed and examined but was unsatisfactory for evaluation of epithelial abnormality. The reasons the test was considered unsatisfactory are given in the report (e.g., too few cells were collected). PRacTice PoinT Unsatisfactory tests are mostly due to cervical sampling and specimen collection issues. The Bethesda (2001) diagnostic categories are as follows: Negative for Intraepithelial Lesion or Malignancy (NILM) Epithelial Cell Abnormality Other

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Pap tests interpreted as negative for intraepithelial Lesion or Malignancy indicate that the test was satisfactory and that the woman should continue with routine screening, or that the test was satisfactory with qualifiers and that it should be repeated in 12 months. The type of qualifier will be given in the report. Tests interpreted as epithelial cell abnormality include both those that represent cervical carcinoma and those that have changes considered to indicate increased risk of cervical carcinoma. Changes indicative of increased risk for cervical carcinoma are reported as follows: Atypical Squamous Cells of Undetermined Significance (ASC-US) Low-Grade Squamous Intrepithelial Lesion (LSIL) Atypical Squamous Cells cannot exclude HSIL (ASC-H) High-Grade Squamous Intraepithelial Lesion (HSIL) Atypical Glandular Cells (ACG) Adenocarcinoma in Situ (AIS)

Managing Women with abnormal Pap Test Results

Table 1 provides guidelines on the management of women based on Pap test results. The TOP guidelines previously recommended that women with ASC-US or LSIL undergo repeat Pap testing every six months for two years (4 tests); if any of those tests was ASC-US or worse, the patient was referred for colposcopy. Since those guidelines were written, key results from the major ASC-US / LSIL Triage study (ALTS) have become available.37 The ALTS study determined that for patients with ASCUS, but not LSIL, testing for high-risk HPV was as sensitive for detecting high-grade precancer compared with repeat cytology, but with significantly fewer referrals for colposcopy for women 29 years and older. In this age group, HPV testing referred 31.2% of women with ASC-US for colposcopy whereas repeat cytology referred 50.1%. HPV testing had the added advantage for women of resolving their follow-up testing much faster. There was no difference in colposcopy referral for younger women. The current TOP guidelines recommend that where HPV testing is available, it be used as a reflex test for women 30 years and older with ASC-US and women 50 years and older with LSIL. In reflex HPV testing the laboratory undertakes an HPV test on leftover liquid-based Pap test sample. When HPV testing is not available, the revised guidelines advise repeat cytology in keeping with recommendations from the American Society for Colposcopy and Cervical Pathology that is, repeat cytology at 6 months and at 12 months.38 If either repeat finding is ASC-US or worse the patient is referred for colposcopy. If both follow-up tests are negative, the patient is returned to routine screening. The one major exception is women younger than 21. (See the Special circumstances section on the following page.) Endometrial cells after age 40 may be associated with benign endometrium, hormonal alterations, and less commonly endometrial or uterine abnormalities. The management recommendation is for clinical correlation. Endometrial biopsy and/or endocervical curettage may be appropriate.

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colposcopy
Colposcopy is a technology used to identify sub-clinical abnormalities of the uterine cervix. The cervix is magnified through a binocular scope with high intensity light. This allows for the identification of abnormalities based upon epithelial density (white epithelium) and vascular patterns (punctuation, etc.). Using these parameters, an area of abnormality can be identified in order to direct a tissue biopsy by one of several available methods (punch biopsy, loop electrosurgical excision, etc.).

Special circumstances
Women who are pregnant The first prenatal visit and the six week postpartum check-up are often used by physicians as opportunities for cervical screening. This may result in over screening. In addition, cervical changes associated with pregnancy and delivery make Pap tests more difficult to interpret. There is no need to perform Pap tests during these visits unless the woman is due for a Pap test or is unlikely to return for screening at an appropriate time. If ASC-US or LSIL is detected during pregnancy, do not repeat the Pap test until six months post-partum. All other findings, especially more advanced lesions, should be managed according to the guidelines. Women who have had a hysterectomy Women who have undergone subtotal hysterectomy and retained their cervix should continue with screening according to the guidelines. The yield of cervical screening is very low in women who have had a hysterectomy for benign disease with complete removal of the cervix and who have no history of biopsy-confirmed cervical precancer or cancer.39 These women do not need to be screened. Women with a history of biopsy confirmed high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ (AIS), or invasive cervical cancer should have vault smears annually thereafter.35 Women younger than 21 years As indicated above under Initiation of Screening, cervical screening is not routinely indicated for women younger than 21 years. If Pap tests are performed in this age group and low-grade dysplastic changes are identified, there is a very high probability they will resolve spontaneously.26 For this reason, recommended follow-up of women younger than 21 years with ASC-US or LSIL is more conservative than for older women. Repeat cytology should not occur until 12 and 24 months. At 12 months, only women with high-grade lesions should be referred for colposcopy. At 24 months, women with ASC-US or greater should be referred for colposcopy. Women with negative repeat Pap tests at 24 months should be returned to routine screening. HPV DNA testing is unacceptable for women with ASC-US or LSIL in this age group. This is because HPV is so frequent in this setting that HPV testing would result in a high rate of colposcopy with a very low probability of cervical carcinoma or progressive disease. If performed inadvertently, the HPV test results should not influence management.

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Women who are estrogen depleted Women who are estrogen depleted may have atrophic cells on the Pap test. These atrophic cells may falsely mimic intraepithelial abnormalities and may be reported as a cytologic abnormality with atrophy. If HPV testing is available, the lab will conduct routine HPV reflex testing for women 50 years and older with ASC-US or LSIL results. If the HPV result is negative, the woman can return to routine screening. If the result is positive, she should be referred for colposcopy. If HPV testing is not available, repeating the Pap test in three months after a course of intravaginal estrogen is recommended. (See Appendix 1 for recommended protocol.) Be sure to indicate on the lab requisition that the patient underwent estrogen stimulation. If the repeat Pap test is negative, the woman can return to routine screening.

optimal Specimen collection

Most cervical precancer and cancer develop in the squamocolumnar junction, also called the transformation zone.10 Because cells in this area of the cervix are always dividing, they are at risk for abnormal changes. The transformation zone is an area characterized by columnar cells proximally, squamous metaplastic cells centrally, and mature squamous cells distally. The ideal sample has both ectocervical and transformation zone cells in adequate numbers to detect abnormalities. The transformation zone can be identified by a change in colour and texture. The squamous epithelium appears pale pink, shiny, and smooth. The columnar epithelium appears reddish with a granular surface. The transformation zone typically recedes into the endocervical canal during menopause, affecting the likelihood of obtaining a squamocolumnar component in a Pap test specimen. Obtaining an optimal specimen requires the clinician to clearly visualize the cervix and sample the endocervical canal. Strict adherence to the sampling technique recommended by the manufacturer can substantially improve the quality of the specimen. In general, during the reproductive years the mid-cycle is the best time for a Pap test. Pap tests in women without a cervix, but with a previous history of high-grade lesions or malignancy, require scraping of the vaginal vault. Cells from the apex of the vault should be collected using the blunt end of a spatula.

PRacTice PoinT A Pap test is a screening test intended to be used in an asymptomatic population with no apparent signs of neoplasia. Specialist referral is essential when the clinician observes an obvious lesion of the cervix and is suspicious of cancer including lesions that are: - Elevated - Keratotic - Ulcerated or covered with bloody necrotic exudate

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Limitations of Screening
Like all screening tests, Pap tests are not perfectly sensitive and a single negative Pap test result does not rule out cervical precancer or cancer. A false negative result occurs when the Pap test fails to detect an abnormality that is present on the cervix. False negative results arise because either the abnormal cells were not collected due to limitations of cervical sampling and specimen preparation, or because abnormal cells were not identified by the laboratory. The sensitivity of conventional cytology to detect high-grade lesions varies widely in published studies between 30% and 87%40 and liquid-based cytology (LBC) does not appear to increase sensitivity substantially, although it does reduce the rate of unsatisfactory samples.41 Repeat screening at regular intervals with either conventional Pap tests or LBC increases the sensitivity of cervical screening and is necessary to provide adequate lifetime protection from cervical cancer. In fact, when the results of two screening rounds are considered together, Pap tests (LBC) alone were as sensitive as Pap tests (LBC) plus HPV testing.42 The Pap test has been so successful at reducing cervical cancer incidence because its sensitivity increases in the context of repeated use. To help overcome the false sense of security that can arise from a false negative test result, it is important to advise women to report unusual vaginal bleeding or discharge including bleeding after intercourse, after menopause, or between menstrual periods. False positive screening test results are also of concern. Given the transient nature of many cervical changes, screening detects many abnormalities that are destined to resolve on their own. The current guidelines are intended to minimize the anxiety and harms associated with screening while helping to assure that clinically significant cervical changes are identified.

Future Directions
The current guidelines have identified a role for oncogenic HPV DNA testing within the screening algorithm in Alberta. In addition to its role in triaging women 30 years with ASC-US and women 50 years with LSIL, HPV testing is being used and studied in other jurisdictions as a routine adjunct to Pap tests and as a primary screening test. The role of HPV testing will evolve as the cohort of HPV vaccinated females approaches the age-group recommended for screening. HPV genotyping is also under study. Different high-risk HPV types have different oncogenic potential. It may one day be possible to use HPV genotyping to improve the detection of cervical cancer and its precursors.

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Reference List

Cervical Cancer

1. Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, TortoleroLuna G, Kjaer SK, Muoz N. Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine. 2008 Aug19;26 Suppl 10:K1-16. 2. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999 Sep:189(1):129. 3. Bosch X, Harper D. Prevention strategies of cervical cancer in the HPV vaccine era. Gynecol Oncol. 2006 Oct;103(1):214. 4. Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006 Mar 30;24 Suppl 1:S4-15. 5. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007 Sep 8;370(9590):890-907. 6. Atlas SJ, Grant RW, Ferris TG, Chang Y, Barry MJ. Patient-physician connectedness and quality of primary care. Ann Intern Med. 2009 Mar 3;150(5):325-35. 7. Kupets R, Covens A. Strategies for the implementation of cervical and breast cancer screening of women by primary care physicians. Gynecol Oncol. 2001 Nov;83(2):186 97. 8. Forbes CA, Jepson RG, Martin-Hirsch PP. Interventions targeted at women to encourage the uptake of cervical screening. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD002834. DOI: 10.1002/14651858.CD002834. 9. National Advisory Committee on Immunization (NACI). Statement on human papillomavirus vaccine. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007 Feb 15;33(ACS-2):1-31. 10. Arbyn M, Herbert A, Schenck U, Nieminen P, Jordan J, Mcgoogan E, Patnick J, Bergeron C, Baldauf JJ, Klinkhamer P, Bulten J, Martin-Hirsch P. European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology. Cytopathology. 2007 Jun;18(3):133-9. 11. Canadian Cancer Societys Steering Committee: Canadian Cancer Statistics 2009. Toronto: Canadian Cancer Society, 2009. 12. Goldie SJ, Kohli M, Grima D, Weinstein MC, Wright TC, Bosch FX, Franco E. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst. 2004 Apr 21;96(8):604-15. 13. Health Canada. Cervical Cancer Screening in Canada: 1998 Surveillance Report. Minister of Public Works and Government Services Canada, 2002. 14. Alberta Cancer Registry, July 7, 2009. 15. Stuart GC, McGregor SE, Duggan MA, Nation JG. Review of the screening history of Alberta women with invasive cervical cancer. CMAJ. 1997 Sep 1;157(5):513-9. 16. Ostr AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993 Apr;12(2):186-92. 17. Bosch FX, de Sanjos S. The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers. 2007;23(4):213-27. 18. Winer RL, Hughes JP, Feng Q, OReilly S, Kiviat NB, Holmes KK, Koutsky LA. Condom use and the risk of genital human papillomavirus infection in young women. NEJM. 2006 Jun 22;354(25):2645-54. 19. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, Young M, Melnick S, Miotti P, Burk R. Cervicovaginal human papillomavirus infection in human

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immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst. 1999 Feb 3;91(3):226-36. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, Wright TC Jr. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA. 2000 Feb 23;283(8):1031-7. Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. 2000 Sep 20;92(18):1500-10. Tam LS, Chan AY, Chan PK, Chang AR, Li EK. Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection. Arthritis Rheum. 2004 Nov;50(11):3619-25. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008 Mar;103(3):6316. Malouf MA, Hopkins PM, Singleton L, Chhajed PN, Plit ML, Glanville AR. Sexual health issues after lung transplantation: importance of cervical screening. J Heart Lung Transplant. 2004 Jul;23(7):894-7. Richardson H, Kelsall G, Tellier P, Voyer H, Abrahamowicz M, Ferenczy A, Coutle F, Franco EL. The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003 Jun;12(6):485-90. Moscicki AB, Shiboski S, Hills NK, Powell KJ, Jay N, Hanson EN, Miller S, CanjuraClayton LK, Farhat S, Broering JM, Darragh TM. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004 Nov 6-12;364(9446):1678-83. Sasieni P, Castanon A, Parkin DM. How many cervical cancers are prevented by treatment of screen-detected disease in young women? Int J Cancer. 2009 Jan 15;124(2):461-4. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ, 2009; 339: b2968. Rogstad KE. The psychological impact of abnormal cytology and colposcopy: transforming a well woman with no symptoms into a patient with fears and anxieties. BJOG. 2002 Apr;109(4):364-8. Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, Prendiville W, Paraskevaidis E. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008 Sep 18;337:a1284. doi: 10.1136/bmj.a1284. Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at different ages: evidence from the UK audit of screening histories. Br J Cancer. 2003 Jul 7;89(1):88-93. Sawaya GF, McConnell KJ, Kulasingam SL, Lawson HW, Kerlikowske K, Melnikow J, Lee NC, Gildengorin G, Myers ER, Washington AE. Risk of cervical cancer associated with extending the interval between cervical-cancer screenings. N Engl J Med. 2003 Oct 16;349(16):1501-9. Melnikow J, McGahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst. 2009 May 20;101(10):721-8. Strander B, Andersson-Ellstrm A, Milsom I, Sparn P. Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study. BMJ. 2007 Nov 24;335(7629):1077.

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35. Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia. Int J Cancer. 2006 Apr 15;118(8):2048-55. 36. Solomon D, Nayar R, editors. The Bethesda system for reporting cervical cytologic: definitions, criteria, and explanatory notes. 2nd ed. New York: Springer-Verlag; c2004. 191p. 37. Sherman ME, Schiffman M, Cox JT; Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study Group. Effects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst. 2002 Jan 16;94(2):102-7. 38. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 ASCCP-Sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis. 2007 Oct;11(4):201-22. 39. Pearce KF, Haefner HK, Sarwar SF, Nolan TE. Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med. 1996 Nov 21;335(21):1559-62. 40. Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, Matchar DB. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000 May 16;132(10):810-9. 41. Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, Ghiringhello B, Giorgi-Rossi P, Minucci D, Parisio F, Pojer A, Schiboni ML, Sintoni C, Zorzi M, Segnan N, Confortini M. Accuracy of liquid-based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ, doi:10.1136/bmj.39196.740995.BE (published 21 May 2007.) 42. Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, Gilham C, Baysson H, Roberts C, Dowie R, Desai M, Mather J, Bailey A, Turner A, Moss S, Peto J. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol. 2009 Jul;10(7):672-82.

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Toward Optimized Practice (TOP) Program
Arising out of the 2003 Master Agreement, TOP succeeds the former Alberta Clinical Practice Guidelines program, and maintains and distributes Alberta CPGs. TOP is a health quality improvement initiative that fits within the broader health system focus on quality and complements other strategies such as the Primary Care Initiative and the Physician Office System Program. The TOP program supports physician practices, and the teams they work with, by fostering the use of evidence-based best practices and quality initiatives in medical care in Alberta. The program offers a variety of tools and outreach services to help physicians and their colleagues meet the challenge of keeping practices current in an environment of continually emerging evidence.

To Provide Feedback
The TOP program encourages your feedback. If you need further information or if you have difficulty applying this guideline, please contact: Toward optimized Practice Program 12230 - 106 Avenue NW Edmonton, AB T5N 3Z1 T 780.482.0319 TF 1.866.505.3302 F 1.866.895.5661 Email: cpg@topalbertadoctors.org

cervical cancer - February 2000 Revised - January 2003 Revised - February 2006 Revised - February 2007 Revised - october 2009

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Appendix 1

Cervical Cancer

Recommended Management of Women with aSc-US in the Background of atrophy when HPV Testing is not available
Recommended Management: If the laboratory recommendation is that the Pap test be repeated after a course of estrogen therapy (this may accompany an ASC-US diagnosis), one of the following forms of estrogen should be prescribed: a) Estrogen intravaginal cream: 1 g 2 to 3 times per week (or every other day). Repeat Pap test no sooner than three months after the initial Pap test. Estrogen cream should be discontinued one week before scheduled Pap test (to allow time for it to be cleared from the cervical area) b) Estring (intravaginal estradiol ring) insert as deeply as possible into the upper third of the vagina. The ring does not need to be removed in order to do the repeat Pap test. Repeat Pap test no sooner than 3 months after the initial Pap test c) Vagifem (estradiol tablets): 1 tablet (inserted in vagina using the applicator) 2 to 3 times per week. Repeat Pap test no sooner than three months after the initial Pap test. Vagifem should be discontinued one week before scheduled Pap test (to allow time for it to be cleared from the cervical area) contraindication to intravaginal estrogen: Women with a prior history of hormone receptor positive breast cancer offered intravaginal estrogen for the management of atrophic Pap tests should be informed of the theoretical, but unproven, risk of augmenting breast cancer recurrence. Other potential contraindications are described in the manufacturers information.

Produced by ACCSP Colposcopy Quality Improvement Committee 2005.04.21 Approved by the Guideline Working Group on Cervical Cancer Screening 2009

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