1. Cervical Cancer Screening and HPV
Leslie Ablard, M.D.

2. Cervical Cancer Incidence/Prevalence Signs & Symptoms
3rd most common GYN cancer in developed world
11,270 new cases in 2009
4,070 deaths in 2009
Most common GYN cancer in developing countries
500,000 new cases annually
240,000 deaths annually
Signs & Symptoms
Abnormal Vaginal Bleeding
Postcoital Bleeding
Vaginal Discharge
(watery, mucoid, purulent, malodorous)

3. Cervical Cancer Risk Factors
Early onset of sexual activity
Multiple sexual partners
High-risk sexual partner
History of sexually transmitted diseases
Smoking (not adenocarcinoma)
High parity
Immunosuppression
Low socioeconomic status
Prolonged use of oral contraceptives
Hx of vaginal or vulvar cancer
Vast majority of cases are caused by persistent high risk HPV infection
Most common Histologies
Squamous Cell Carcinoma
Adenocarcinoma
Adenosquamous

4. Human Papillomavirus
Lifetime cumulative risk of acquiring HPV in sexually active persons = 80%
Spectrum of HPV
Condyloma Acuminata
Cervical Dysplasia
Cervical Cancer
> 150 different types of the virus
15 High Risk Types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82)
16, 18  > 70% all cervical cancers
6, 11  90% genital warts
HPV Vaccine – Gardasil ®
Active against 16, 18, 6, 11
FDA approved in US for girls & boys ages 9-26

5. Human Papillomavirus 6.2 million new infections per year
20 million active infections (prevalence)
330,000 cases of CIN 2, 3
11, 400 cases of cervical cancer
LEEP/Cone doubles risk of
PTL and IUGR

6. Human Papillomavirus HPV 16, 18 Association with abnormal pap tests
Rate 16 18
Total/yr
ASC
5.1%
13% 6%
581,000
LSIL
2.6%
24%
10%
530,000
HSIL
0.7%
61% 7%
285,100

7. Human Papillomavirus External Genital Warts
500,000-1,000,000 new cases per year
240,000 initial office visits per year
1% of sexually active US population between yrs old
1/3 of all STI dollars annually

8. Human Papillomavirus HPV associated cancer deaths Site Total Cancers
AF (%)
Attributable Cases
Cervix
11,150
100%
Penis
1,280
40%
512
Vulva/Vagina
5,630
2,252
Anus
4,650
90%
4,185
Airway
24,540
26%
6,380
Total
47,250
12%
24,479

9. HPV ACIP recommendations
Females with abnormal pap results or genital warts should be given one of the two vaccines if they are in the indicated age group to prevent from types she has not been exposed to previously

10. ACOG Bulletin 109
Cervical cancer is one of the most preventable cancers
In the past 30 yrs, Pap test has reduced cervical cancer deaths by over 80%
New ACOG screening guidelines published in December 2009

11. Natural History of Cervical CA
Persistent infection with HPV is a prerequisite for the development of cervical cancer and its precursors
At least 80% of women acquire genital HPV infection at some point in their lifetime
HPV most common in teenagers and women in their early 20s, prevalence decreases with age
Most HPV infected women will not develop significant cervical abnormalities

12. Natural History of Cervical CA
Most HPV infections become undetectable in an average of 8-24 months
Most CIN lesions resolve spontaneously in adolescents and young women
HPV in older women is more likely to reflect persistent infection acquired in the past
HPV type and persistence of infection are the most important determinants of progression

13. Clearance of HPV @ 48 months – 50% CIN 2,3 @ 60 months- 60% CIN 2,3
@ 1 yr- 60% clear
35% persistent
3% HGSIL

14. When should Pap screening Begin?
New Recommendations:
Begin at age 21
Prior guidelines begin at age 21 or 3 yrs after onset of intercourse
Why the change?
HPV infection and minor cytological abnormalities common in young women
Most are cleared in 1-2 yrs
Cervical cancer is extremely uncommon less than age 25

15. Invasive Cervical Cancer in Adolescents- SEER Registry
0.1% of cervical cancer occurs before age 21 yrs
British data suggests that those cancers that occur aren’t detected through screening
1-2 cases/ 1,000,000 girls age 15-19
Audit of UK cervical cancers found no benefit of screening women yrs old
US ONLY COUNTRY TO DO ANNUAL PAPS

16. Consequences of Screening Adolescents
Treatment for lesions destined to resolve without therapy
Treatment for CIN (LEEP) increases risk of
Preterm Birth (OR 1.7)
LBW (OR 1.8)
PPROM (OR 2.7)
DOUBLES RISK!!!

17. Frequency of Cervical Cytology Screening
Every 2 yrs for women age 21-29
Every 3 yrs for women age 30 or greater (after 3 consecutive negative paps or with concurrent neg HR HPV)
Exceptions to extended screening
HIV
Twice first yr, annually thereafter
Immunocompromised
DES exposed
History of CIN 2,3 or cancer
Annual screening for 20 yrs after initial post-treatment suvelliance

18. Screening Interval Why change?
Supported by both empirical data and mathematical modeling studies
31,728 women age yrs in National Breast Cervical Cancer Early Detection Program
Rate of CIN decreased with increasing number of sequential negative Paps
If 3 consecutive negative Pap tests, prevalence of CIN 3 was 0.019% with no cases of cancer

19. When to discontinue screening
Age 65 or age 70 in women with 3 consecutive negative Paps and no abnormal Paps in the past 10 yrs
ACOG guidelines accept either USPSTF (65) or ACS (70) age cutoff
If screening is discontinued, risk factors should be reassessed during the annual examination

20. When to discontinue screening
Why the change?
In well screened older women with HSIL rates are low and cervical cancer is rare
Most cases of cervical CA in US women older than 65 yrs are in inadequately screened women
Cervical cancer develops slowly and risk factors decrease with age

21. Consequences of screening older women
False-positive cytology due to vaginal atrophy
Additional procedures
Anxiety
Unnecessary expense
Difficulty in getting satisfactory samples
Vaginal atrophy
Cervical stenosis

22. Discontinue Screening Following Hysterectomy?
Discontinue screening in women with no history of CIN 2,3
Most abnormal test results are falsely positive
In one study, only 1.1% had cytological abnormalities, no VaIN 3 or cancer
Continued screening is not cost-effective, causes anxiety, and leads to over treatment
HAVE TO DOCUMENT NO CIN 2,3 ON PATH

23. What is a Pap Smear? “Papanicolaou test” - 1941
Dr. Babes & Dr. Papanikolaou
80% decrease in rates of cervical cancer in developed countries over last 30 yrs due to widespread screening
A sample cervix cells from transformation zone.
junction of endocervix and ectocervix
Use of spatula +/- cytobrush, broom stick
2 types – conventional, liquid-based
Send for cytologic interpretation

24. How to perform a Pap smear…
Conventional smear
direct application of cells to a slide
Liquid Based smear
90% of all Pap smears in US
Transfer cells to a liquid preservative. Liquid processed in laboratory and transferred to a slide

25. Bethesda System (2001) Classification
Specimen Adequacy
Is the transformation zone present ??
Negative for intraepithelial lesion or malignancy (NIL,NILM, NIELM)
Squamous Cell
Atypical squamous cells
Undetermined Significance (ASC-US)
Not exclude High Grade (ASC-H)
Low Grade Squamous Intraepithelial lesion (LSIL) – encompasses CIN I
High Grade Squamous Intraepithelial lesion (HSIL) – encompasses CIN II & III
Squamous Cell Carcinoma
Glandular Cell
Atypical Glandular cells (AG)
Atypical Endocervical Cells
Atypical Endometrial Cells
Atypical Glandular Cells Not Otherwised Specified (AG-NOS)
Favors Neoplasm
Adenocarinoma In Situ (AIS)
Adenocarcinoma

26. Management of Abnormal Paps
ASC-US
Reflex HPV testing if age > 21
If positive for high risk HPV (HRHPV)  Colposcopy
If negative  Repeat Pap and HPV in 1 year
Adolescents (<21)  Repeat Pap/HPV in 12 months
HGSIL at 12 months - Colpo
If ASC or greater in 12 additional months
(total 24 months)- Colpo
Pregnancy with HR HPV- acceptable to defer pap/colpo post partum

27. Management of Abnormal Paps
ASC-H
Refer to colposcopy
If CIN 2,3- treat
If no CIN 2,3
Cytology 6, 12 months OR HPV at 12 months
ASCUS or greater or HPV + - Colpo

28. Management of Abnormal Paps
LSIL
Adolescents (<21)  Repeat Pap in 12 months- If ASCUS or greater total 24 months- Colpo
Pregnancy- acceptable to defer pap/colpo post partum
Everyone else  Colposcopy
Non pregnant and NO lesion – ECC Preferred
Unsatisfactory ECC Preferred
Satisfactory with Lesion ECC Acceptable
No CIN 2,3- Cytology at 6,12 months OR HPV at 12 mo
ACUS or +HPV- Colpo
CIN 2,3- Treat per guidelines

29. Management of Abnormal Paps
HSIL
LEEP or Refer to colposcopy
No CIN 2,3
Unsatisfactory- Diagnostic Excisional Procedure (LEEP)
Satisfactory
Colpo and cytology for 6 months x 1 yr
Diagnostic Excisional Procedure (LEEP)
CIN 2,3
Treat per guidelines
Adolescents
- Persists for 24 months- LEEP

30. Management of Cervical Dysplasia
Glandular Cells;
Atypical Glandular Cells
Subtype: Atypical Endometrial Cells
Endometrial biopsy (EMB), endometrial currettage (ECC)
If no endometrial pathology  Colposcopy
Rest of Subtypes (AGC-NOS, endocervical, favor neoplasm)
Colposcopy
EMB if over 35 or at risk for Endometrial Cancer
ECC
HPV DNA testing
Adenocarcinoma in situ
Colposcopy, EMB & ECC
Diagnostic Excisional Procedure / Total Hysterectomy?

31. Basic Components of Colposcopy
Prepare your patient
Obtain informed consent and answer her questions
Assure her you will attempt to minimize pain (often a consuming worry)
Make sure to know the pregnancy status of your patient
Ibuprofen 800 mg may be offered prior to procedure or the night before and morning of the procedure, although its efficacy is questionable

32. Basic Components of Colposcopy
Quickly examine the vulva for obvious condylomata or other lesions
Warm the speculum with water or water soluble lubricants and insert the speculum
Examine the cervix
Is the cervix inflamed or infected-looking
An active cervicitis confounds colposcopic detail
Do cultures if necessary
Repeat Pap only if this is critical information
Even a correctly performed Pap smear may irritate the cervix and often causes bleeding Gently blot (not wipe) away any excess mucous using normal saline
Look for leukoplakia and abnormal vessels

33. Basic Components of Colposcopy
Generously place 3-5% acetic acid on the cervix-
(Acetowhite correlates with high nuclear density)
Mild acetowhite epithelium < Intensely acetowhite
No blood vessel pattern < Punctation < Mosaic
Diffuse vague borders < Sharply demarcated borders
Follows normal contours of the cervix < "humped up"
Normal iodine reaction (dark) < Iodine-negative epithelium (yellow)
Leukoplakia - usually a very good (condylomata) or a very bad sign
Atypical vessels - a hallmark of cancer

34. Transformation Zone Nearly all cervical neoplasia occurs in the TZ
This is even true of the adenocarcinomas, which are often associated with adjacent high-grade squamous disease
This is because it is the reserve cells undergoing metaplasia that are vulnerable to various carcinogens such as HPV
Metaplasia is at peak activity during adolescence and first pregnancy, it is understandable that early age on sexual activity and first pregnancy are known risk factors for cervical cancer
Given a particular lesion, the more severe disease tends to be cephalad in the TZ, where the epithelium is least mature
In order that a colposcopic exam may be deemed “satisfactory” or “adequate,” the TZ must be seen in its entirety, all the way up to the columnar epithelium, 360°, which means that all areas involved in squamous metaplasia have been visualized

35. Basic Components of Colposcopy
“Satisfactory” and “Adequate”
Entire TZ visualized
All lesions seen in their entirety
Tools to help
Endocervical Speculum
Small Q-tip
If not-----ECC

36. Lugol’s or Schiller’s Test
Stains Glycogen
May be used by the beginning colposcopist or at any time when further clarification of potential biopsy sites is necessary
Iodine staining does not interfere with histology
Lugol's solution is often very helpful on the vagina and proximal vulva (non- keratinized skin)
It can be used to thoroughly and simultaneously examine the entire vagina for glycogen-deficient areas, which correlate with HPV and/or dysplasia in non-glandular mucosa
It is often reserved for difficult cases when a non-cervical source of cervical Pap smear atypism is suspected (as in "normal cervical colposcopy" with dysplasia on Pap smear or normal ECC histology)

37. Summary Historically we have over-screened and over- treated women
ACOG 2009 guidelines are based on sound mathematical and epidemediologic data
HPV type and Persistence is the greatest predictor of the progression of dysplasia
Colposcopy beginners rule- Biopsy everybody

38. Thank You