Screening for Cervical Cancer. Grand Rounds 1/16/13 Meggan Linck

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1 Screening for Cervical Cancer Grand Rounds 1/16/13 Meggan Linck

2 Cervical Cancer Worldwide 2 nd most common and 5 th deadliest U.S. 8 th most common 80% occur in developing world Median age at diagnosis is 48 Hispanic women are significantly more likely to be diagnosed

3 Incidence of Cervical Cancer Screening guidelines have led to a 50% decrease in last 30 yrs 1975 rate was 14.8 per 100,000, in 2008 rate has decreased to 6.6 Mortality has decreased similarly from 5.55 to 2.38 Cervical cancer is much more common in places where screening programs aren t in place Majority of cervical cancer occurs in women who were inadequately screened Of new cases estimated that 50% were never screened and 10% weren t screened in previous

4 United States-Less than 2.4 deaths per 100,000

5 New Guidelines ACS, ASCCP, ASCP have updated joint guidelines on cervical cancer screening and have sent a recommendation to the U.S. Preventative Task Force Screening can be performed by liquid-based or conventional screening techniques

6 What is the most carcinogenic HPV type? A) HPV 16 B) HPV 18 C) HPV 11 D) HPV 6

7 HPV Two types of HPV-Oncogenic vs. Nononcogenic or high-risk versus low-risk HPV accounts for 90+% cases of cervical cancer HPV infection can be either transient or persistent Persistent infection at 1-2 years predicts CIN 3 progression or cervical cancer Not understood completely which infections will persist, but HPV type appears to be a significant factor HPV 16 is most carcinogenic with 55%-60% of the cases of cervical cancer HPV 18 is second most with 10%-15% of cases Other types account for remainder of cases

8 HPV cont. Increased risk with cigarette smoking, immunodeficiency and +HIV status HPV infection most common in teenagers and women in their 20 s. Most women in this age group have an effective immune system that will clear the infection in an average of 8 mo. with resultant resolution of cervical neoplasia Course of HPV infection is similar in those over 30, however because most of these cases represent persistent infection HGSIL is more common in this age group

9 HPV cont. CIN 1 infection usually represents acute infection and should be treated with conservative management CIN 2 controversial because of uncertainty about diagnosis as well as treatment CIN 3 represent high risk of progression to cervical cancer with risk of 30% at 30 years Progression of CIN 3 to invasive cancer 3-7 years

10 HPV genotyping Two different tests for genotyping of HPV, one tests for HPV 16 only the other for 16,18 or both

11 When should you start screening? A) When a woman becomes sexually active B) Age 18 C) If she has more than 5 partners D) Age 21

12 Screening Guidelines-When to start Screening should begin at age 21 regardless of age of first sexual intercourse Only 0.1% of cervical cancer cases are found in this age group Studies have shown that screening in this age group hasn t decreased the rate of cervical cancer Positive screening results at this young age may cause stress and undue financial burden along with reproductive challenges

13 Table 1. Screening Methods for Cervical Cancer: Joint Recommendations of the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology Women younger than 21 years-no screening Women aged years-cytology alone every 3 years Women aged years-human papillomavirus and cytology co-testing (preferred) every 5 years or Cytology alone (acceptable) every 3 years Screening by HPV testing alone is not recommended Women older than 65 years-no screening is necessary after adequate negative prior screening results Women with a history of CIN 2, CIN 3 or adenocarcinoma in situ should continue routine age-based screening for at least 20 years Women who underwent total hysterectomy-no screening is necessary Applies to women without a cervix and without a history of CIN 2, CIN 3, adenocarcinoma in situ, or cancer in the past 20 years Women vaccinated against HPV Follow age-specific

14 How often to screen ages Few studies have been done that address this specifically One showed that in this age group, in those screened every 3 years instead of every 2 years costs from colposcopy would be decreased (176,000 vs 134,000 procedures per 100,000) and cervical cancer risk (39 vs 37 cases/100,000) Because this risk is minimal and costs from colposcopy can be cut so drastically recommending screening every 3 years in this age group

15 How well are we doing? In a 2012 telephone survey-between never had a pap increased from 26.3% in 2000 to 47.5% in 2010 Those reported as having a pap test in the last 12 months decreased from 65% to 41.5% For those between the ages of those reporting having testing in last 12 months decreased from 78.1% to 67% However in this age group amount of women reporting never had screening increased from 6.6% to 9%

16 How often to screen ages Co-testing should be performed every 5 years, if cervical cytology alone is performed it should be done every 3 years Co-testing shows lower cancer incidence with decreased costs from procedures Pooled analysis of European study showed a 0.28% risk of CIN 3 after negative co-testing and 0.51% risk after negative cytology alone at 6 year mark Population study of 331,818 women showed rate of cervical cancer of 0.016% 5 years following negative co-testing and 0.018% 3 years following negative cytology

17 Cytology alone is also acceptable in this age group and should be performed every 3 years Consensus review by ACS, ASCCP, and ASCP suggested that there is no need to alter screening based on previous negative results Matched case control study showed no difference in invasive cancer risk based on prior negative results

18 HPV testing is more sensitive, but less specific than cytology Co-testing is not recommended for those less than 30 because of the high rate of high-risk HPV infection and low risk of cervical cancer in this group which would result in more invasive testing without decrease in cervical cancer incidence Women over age 30 with both negative cytology and negative HPV testing have been shown to be low risk for developing CIN 2-3 in next 4-6 years risk was found to be much lower than in those with only negative cytology

19 Co-Testing Based on 3 Randomized Control Trials Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncology Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. New Technologies for Cervical Cancer screening (NTCC) Working Group. Lancet Oncology Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med

20 Co-testing also has a increased rate of detecting adenocarcinoma than cytology alone In a RCT in which 10,154 were randomized to either HPV or pap tests-sensitivity of HPV testing 94.6% vs. 55.4% for pap, specificity was 94.1% vs. 96.8% for pap For both tests sensitivity was 100%, specificity 92.5%

21 Lancet Oncology 2010 High number of the cancer cases in cytology group were adenocarcinomas Also had phase 2 where HPV alone was tested against cytology-similar decrease in rate of CIN 2 to 3 in stage 2 Recommended not using HPV testing in young women as there was overdiagnosis of regressive CIN 2 Recommended using cytology only for HPV + in women age 35 and older Did not give follow up intervals

22 Lancet Oncology 2012 RCT with women tested with co-testing or cytology and then co-testing 5 years later Those women who had co-testing had less CIN 3 and cervical cancer lesions than those that underwent cytology alone No cervical cancer was detected in co-testing group, but 9 were found in cytology group HPV testing leads to identification if CIN 3 lesions that would be missed by cytology alone Much of the attributable effect due to identification of HPV 16 lesions

23

24 These screening recommendations are not meant for patients with cervical cancer, HIV infection, those who are immunocompromised or have a history of exposure to DES in utero CDC-those with HIV have cervical screening 2x in first year after diagnosis (even if diagnosed at age <21) as well as annually afterward-differs from guidelines set by ACS, ASCCP, ASCP No guidelines for those with immunocompromise for other reasons-annual screening at age 21

25 When to stop screening At age 65 if adequate negative results and no history of CIN 2 or higher Adequate negative results defined as 2 negative co-testing results or 3 negative cytology results within previous 10 years with most recent performed in last 5 years Women with CIN 2 or higher screening should be discontinued 20 years after regression or treatment even if exceeds 65 years as metaanalysis showed these patients have 2.8 fold increase risk for cervical cancer in 20 years following diagnosis

26 Cervical cancer in those >65 Represents 19% of new cervical cancer casesmost cases are in those inadequately screened Cervical cancer occurs at a median of years after HPV infection If screening was continued every 3 years until 90 years of age would prevent 1.6 cancer cases and 0.5 deaths per 1,000 No need to start screening with new partner Atrophy corresponds to false positive pap results in postmenopausal patients

27 Post hysterectomy patients With total hysterectomy (removal of cervix) and no history of CIN 2 or higher screening can be discontinued Risk of vaginal cancer is low especially in this population of patients Study of 6,543 women who had a hysterectomy and did not have history of CIN on follow up 1.8% had abnormal pap smear result with 0.12% having VIN on biopsy, no cases of cancer 5,037 had hysterectomy with CIN 3 abnormal cytology in 14% with VIN in 1.7% with one case of cancer

28 Should continue with screening with past history of CIN 2 or higher for 20 years with cytology every 3 years after post treatment follow up Role of HPV testing not clarified

29 HPV testing alone? Recent systematic review showed only marginal benefit with co-testing as compared to HPV testing alone At this point HPV testing is not recommended solely for screening

30 Negative cytology and negative HPV-continue age based screening methods-risk 0.28% for CIN 3 in this population Negative cytology with positive HPV-3.7% of women over age month risk of CIN 3 0.8%-4.1%-did not recommend colposcopy Co-testing-if repeat is same or LGSIL perform colposcopy HPV genotype-if positive for HPV 16 or both 16 & 18 then colposcopy, if negative then repeat co-testing in 12 months if HPV + or LGSIL then colp Recommendations come from cohort studies that show regression rate of 60% at 6 months with above results and in another study regression rate of 67% at 1 year If persists at 1 year progression to CIN 2 or higher 21% at 30 months

31

32

33 HPV vaccine Should be screened like general population Reduction in cervical cancer not expected for another 20 years Vaccine only effective against HPV 16 & 18 which accounts for 70% of cases, but still 30% of cases that are not covered by vaccine Vaccine is approved up to age 26 at what age most women have acquired the virus which makes vaccine less effective Not everybody gets vaccine and with no vaccine registry difficult to distinguish who has received it Long term follow up has not been completed

34

35

36 References ACOG Cervical cancer screening Among Women Ages United States , CDC Weekly, Jan , 61/(51); Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012;13: (Level I) Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. New Technologies for Cervical Cancer screening (NTCC) Working Group. Lancet Oncol 2010;11: (Level I) Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer [published erratum appears in N Engl J Med 2008;359:1637]. N Engl J Med 2007; 357: (Level I)

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