To Smear or Not To Smear

1. To Smear or Not To Smear � DOMMR Week of 9/1/2008 Rozy Mithani

2. Goals Recognize the Criteria for a Screening Test Understand the current recommendations for PAP smear screening and follow-up Recognize the role of HPV in cervical cancer and determine patients who are candidates for Vaccination

3. Types of Prevention Primary prevention: prevention of disease before it starts i.e. immunization Secondary prevention: detection of diseases at an earlier, presymptomatic stage, so as to decrease morbidity/mortality i.e. pap smears Tertiary prevention: preventing complications or undue morbidity in established symptomatic chronic disease i.e. ACE inhibitors in CHF

4. Good Candidates Important cause of morbidity and mortality High enough prevalence false-positive (increased in rare conditions) and false-negative values Effective screening test/procedure must exist Test should be low risk and acceptable to individuals undergoing the test Benefit to early intervention

5. Cervical Cancer  as a Screening Candidate Important cause of morbidity and mortality ~500,000 new cases, ~250,000 cancer-related deaths High enough prevalence: 10th cause of cancer death Effective screening test/procedure must exist Duh! Test should be low risk and acceptable to individuals undergoing the test Benefit to early intervention 5 year Survival: localized 92% vs. distant 13% CIN to CIS transit time 3.8-5.7 years

6. Risk Factors Early onset of intercourse Multiple sexual partners h/o STD Smoking only nonsexual behavior correlated with dysplasia/cancer Four-fold increase

7. Doing the Deed Sample the transformation zone/SCJ columnar endocervical epithelium to squamous (ectocervical) epithelium Combined technique: Spatula to sample the ectocervix Cytobrush to sample the endocervix

8. Papanicolaou Test Sensitivity of a single Pap: 60-80% recommend annual Pap smears x 2-3 normal before going to every 3 years Meta-analysis: 1.8 million women Different Screening Intervals: (estimated reduction in incidence of invasive disease) 5 years (84%) 3 years (91%) 2 years (93%) 1 year (94%)

9. The more the merrier � right? No evidence annual screening has better outcomes than screening every 3 years Majority: never been screened not screened within the past 5 years Other: don�t receive appropriate followup after an abnormal Pap

10. Liquid-based cytology No evidence Liquid based is better Fewer unsatisfactory specimens air-drying artifact cells distributed more evenly less potential for cellular debris Ability to perform reflex HPV testing Check for other STIs May be better with glandular lesions

11. Screening Recommendations

12. Can�t we all just get along?

13. The USPSTF strongly recommends screening for cervical cancer in women who have been sexually active and have a cervix. Rationale: Good evidence this reduces incidence of and mortality from cervical cancer Indirect evidence suggests most of the benefit can be obtained by beginning screening within 3 years of onset of sexual activity or age 21 (whichever comes first) and screening at least every 3 years

14. The USPSTF recommends against routinely screening women > 65 for cervical cancer if they have had adequate recent screening with normal Pap smears and are not otherwise at high risk for cervical cancer Rationale: Limited evidence to determine the benefits of continued screening in women older than 65 Yield of screening is low due to the declining incidence of high-grade cervical lesions after middle age. Fair evidence that screening women older than 65 is associated with an increased risk for potential harms, including false-positive results and invasive procedures.

15. You down with HPV � yeah you know me Causes 99% of cervical cancer Oncogenic strains: HPV 16 and HPV 18 = 70% Genital warts: HPV 6 and HPV 11 DNA integrates into host genome ? Active expression of proteins ? Bind to & eliminate tumor suppressor genes Necessary but insufficient precursor Host factors

16. HPV Younger Pts: Increased prevalence but transient Older Pts: Decreased prevelance but higher risk of progressing to cervical neoplasia Insufficient evidence to screen routinely for HPV in <30 y/o data suggest HPV-DNA testing as f/u to low-grade atypia HPV + but Cytology � Repeat combined testing 12 months

18. Discontinuation of cytological screening after total hysterectomy for benign disease (e.g., no evidence of cervical neoplasia or cancer) is appropriate given the low yield of screening and the potential harms from false-positive results in this population. Clinicians should confirm that a total hysterectomy was performed ACS and ACOG recommend continuing cytologic screening after hysterectomy for women with a history of invasive cervical cancer or DES exposure due to increased risk for vaginal neoplasms, but data on the yield of such screening are sparse.

19. The USPSTF recommends against routine Pap smear screening in women who have had a total hysterectomy for benign disease. Rating: D Rationale: Fair evidence that the yield of cytologic screening is very low in women after hysterectomy Poor evidence that screening to detect vaginal cancer improves health outcomes

20. Newer technologies, such as the liquid-based cytology (e.g., ThinPrep�), may have improved sensitivity over conventional Pap smear screening, but at a considerably higher cost and possibly with lower specificity. Unlikely to be cost-effective unless used with screening intervals of 3 years or longer. Liquid-based cytology permits testing of specimens for HPV, which may be useful in guiding management of women whose Pap smear reveals atypical squamous cells. HPV DNA testing for primary cervical cancer screening has not been approved by the FDA and its role in screening remains uncertain.

21. The USPSTF concludes that the evidence is insufficient to recommend for or against the routine use of new technologies to screen for cervical cancer. Rating: Inconclusive Rationale: Poor evidence to determine whether new technologies, such as liquid-based cytology, computerized rescreening, and algorithm based screening, are more effective than conventional Pap smear screening in reducing incidence of or mortality from invasive cervical cancer. Cannot determine whether the potential benefits of new screening devices relative to conventional Pap tests are sufficient to justify a possible increase in potential harms or costs.

22. The USPSTF concludes that the evidence is insufficient to recommend for or against the routine use of human papillomavirus (HPV) testing as a primary screening test for cervical cancer. Rationale: Poor evidence to determine the benefits and potential harms of HPV screening as an adjunct or alternative to regular Pap smear screening. Trials are underway that should soon clarify the role of HPV testing in cervical cancer screening.

23. Bethesda � is she cute? Most abnormal Paps due to Infection/Low Estrogen Distinguishes between: Benign cellular changes (infection, reactive, or reparative) Truly atypical changes (ASCUS or AGUS) which are more likely to indicate precancerous/cancerous lesion Replaces CIN 2 & 3 with HGSIL CIN 1 with LGSIL

25. Cervical Cancer Squamous Cell 80-90% SCJ: squamous epithelium of the ectocervix and the columnar epithelium of the endocervix Adenocarcinoma 10-20% develops from the columnar epithelium of the endocervix

26. ASC �Atypical Squamous Cells ASC-US: uncertain significance Repeat Cytology HPV testing + ? colposcopy - ? follow-up with repeat Pap smear 1 year Colposcopy ASC-H: possible HSIL perform a colposcopy with endocervical assessment

29. Colposcopy Magnify epithelium after 3% acetic acid Highlights abnormal vascula patterns/thickened epithelium i.e. ASC-US

30. LSIL Low-grade squamous intraepithelial lesion Early changes in the size and shape of the cells Often associated with the presence of HPV Options: Colposcopy HPV testing repeat Pap

32. HSIL High-grade squamous intraepithelial lesion (CIN 2 or CIN 3) Precancerous Options: Colposcopy or Loop excision Pap x 3 normal then resume q 3 years

34. AGC � Atypical Glandular Cells Cells that produce mucus Located in the cervix or uterus Higher risk for cervical cancer perform a colposcopy

36. What if it�s Abnormal? Excisional therapy: Extent or type of cervical abnormality is unclear Allows for microscopic review and margins Ablative therapy: less concern for cancer or extent of the abnormal tissue

37. Excision Tissue sample and Complete excision of lesion i.e. visible lesion Diathermy Loop Excision: Loop electrosurgical excision procedure (LEEP) or large loop excision of the transformation zone (LLETZ) Electric current Cervical cone biopsy (conization): Done in the OR

38. Ablation Destroys abnormal cervical tissue Cryosurgery: Liquid nitrogen or carbon dioxide freezing technique that destroys the surface layer i.e. CIN Laser ablation: High intensity light beam Done in the OR Electro-diathermy: heat producing electric current

39. Gardasil Vaccine Against HPV 6, 11, 16, 18 3 Doses: 0, 2, 6 months Ages: 9-26 y/o FUTURE II study: >12,000 women 15-26 y/o Conclusion: In women not previously infected with HPV-16 or HPV-18, vaccine recipients had lower occurrence of high-grade CIN Reduced vulvar and vaginal intraepithelial neoplasia and anogenital disease Vaccine most effective before HPV exposure

40. Summary Recognize the Criteria for a Screening Test Important cause of morbidity and mortality High enough prevalence Effective screening test/procedure must exist Test should be low risk and acceptable to individuals undergoing the test Benefit to early intervention Understand the current recommendations for PAP smear screening and follow-up Start within 3 years of onset of sexual activity or age 21 Screening at least every 3 years Stop at age 65-70 Recognize the role of HPV in cervical cancer and determine patients who are candidates for Vaccination Causes 99% of cervical cancer Approved for age 9-26

41. Example #1 315 y/o Female with ASC-US on Pap last month What is the next most appropriate test? A: repeat cytology at 6 months B: colposcopy C: HPV testing

43. Example #2 72 y/o Female presents for annual screening. She has had regular medical care. Which of the following is appropriate? A: Perform a Pap today B: Perform a Pap next visit so that you can bill again C: Inform her that she no longer needs a Pap smear

44. Can�t we all just get along?

45. Example #3 35 y/o Female with no prior h/o abnormal Pap here for f/u of Pap performed last week. Results: HSIL What is the next appropriate step? A: repeat Pap today B: HPV testing C: Colposcopy

47. Questions?