DOMMR

1. Week of 9/21-9/24 DOMMR

2. Objectives Discuss the epidemiology of cervical cancer and methods of screening Will focus specifically on the Pap Smear as a screening method Review the Bethesda Classification System for reporting cervical cytology Discuss when cervical cancer screening should start, how frequent it should be done, and how long to continue Review the interpretation of cytology seen on pap smears

3. Cervical Cancer - Epidemiology A disease of sexually active women Risk factors: HPV infection Cigarette smoking Immunosuppression Three or more lifetime sexual partners or 1st intercourse before Age 18 Maternal DES (diethylstilbesterol) exposure during pregnancy A previous abnormal Pap smear 2nd most common female cancer worldwide Most often a disease of adult women, rarely seen in adolescents Most common in developing countries In 2008, 11,070 new cases of invasive cervical cancer in the US 3870 expected cancer related deaths

4. Cervical Cancer Cervical intraepithelial neoplasia (CIN) is the pre-invasive dysplasia of cervical epithelial cells Precursor of malignant disease Categorized by depth and atypicality of cells in the cervical epithelium (CIN 1-3) Slow malignant transformation leads to a long latency period Some low grade lesions may regress spontaneously Rates of regression as high as 75% at 5 yrs in adults and up to 91% at 3 yrs in adolescents

5. Cervical Cancer Screening The Pap smear introduced in 1941 by George Papanicolau who initially used this method to study the estrous cycle of guinea pigs Used to identify abnormal cells taken from the transformation zone (junction of ecto- and endocervix) Between 50-60 million pap smears done annually in the US 3.5 million are read as abnormal 2.5 million undergo diagnostic colposcopy An Australian study showed that a 15yr female has a 77% lifetime risk of undergoing at least one colposcopy Thin layer (or liquid-based) cervical cytology is also used in the US as another screening method SurePath, ThinPrep Cervical dysplasia and cancer arise at transformation zoneCervical dysplasia and cancer arise at transformation zone

6. Pap Smear A screening test (used for asymptomatic patients), not diagnostic (to confirm a disease) Cannot be used for a definitive diagnosis or to initiate treatment Functions to screen for cellular abnormalities associated with an increased risk for cervical cancer Goal is to distinguish between lesions likely to progress to carcinoma verses those that aren’t Sensitivity and specificity are widely variable Liquid based cytology has theoretical advantages (lower incidence of inappropriate fixation and drying artifact) but never proven to have better accuracy Can include sources of error in need longer lectureCan include sources of error in need longer lecture

7. Pap Smear The pap smear has never been evaluated in a randomized controlled trials Only observational studies have given any evidence of improving mortality from cervical cancer Screening implemented in Finland, Sweden, Iceland, but not Norway Before screening – all with similar rates of cervical cancer After screening – all countries but Norway saw a decrease in incidence of cervical cancer In the US, invasive cervical cancer is more likely from failure to perform appropriate screening rather than inaccuracies in screening >50% of women with cervical cancer have never had screening and another 10% have not had a pap smear in the last 5 yrs

8. Pap Smear Pap smear obtains cytologic results, but not able to assess tissue structure Diagnosis of CIN or cervical carcinoma requires a tissue sample, which is obtained by biopsy Bethesda system standardized terminology for reporting cervical cytology First introduced in 1988, revised in 2001 Now reports on the adequacy of the specimen ASCUS category changed to ASC (ASC-US, ASC-H) AGUS category changed to AGC Now tells origin of cell and further subcategorizes

9. Bethesda Classification System Atypical Squamous Cells (ASC) Unspecified (ASC-US) - includes unspecified and favors benign/inflammation Cannot exclude HSIL (ASC-H) Low-grade squamous intraepithelial lesion (low-grade SIL) Cellular changes associated with HPV Mild (slight) dysplasia/CIN 1 High-grade squamous intraepithelial lesion (high-grade SIL) Moderate dysplasia/CIN 2 Severe dysplasia/CIN 3 Carcinoma in situ/CIN 3 Atypical Glandular Cells of Uncertain Significance (AGC) AGC distinguishes cell origin: endocervical, endometrial, or NOS Further differentiated into: favors neoplasm, Adenocarcinoma in situ (AIS), or adenocarcinoma

10. Bethesda classification 2001 revision now subcategorizes ASC into ASC-H and ASC-US ASC-H comprises 5-10% of ASC overall Subclassification hopefully allows physicians to more rapidly evaluate a patient who may have CIN 2, 3 There is some correlation between pap smear cytology results and biopsy results i.e. LSIL cytology would yield CIN 1 histology Of patients with LSIL, 45%?CIN 1, 33% had no identifiable pathology, 16% had CIN 2, 3 Most common cytologic abnormality is ASC-US, seen in 3-4% of pap smears LSIL seen in 2% of pap smears, HSIL in 0.5-1% of pap smears

11. Atypical Glandular Cells Important to differentiate AGC (atypical glandular cells) from ASC (atypical squamous cells) AGC is a significant marker for neoplasia AGC associated with premalignant or malignant lesion 10-40% of the time All with AGC should be referred for colposcopy Women >35yrs should also have endometrial biopsy

12. Pap Smears When should screening start? At age 21 or 3 yrs after first sexual intercourse (whichever comes first) How often should I screen for cervical cancer? Originally, annual screening was implemented in the US More recently this frequency has been reconsidered

13. Frequency of pap smear screening “Protection from cervical cancer remained high up to 3 yrs after a negative pap smear” “Rates of severe cervical cytology (CIN 2 or worse) within 2 yrs of a normal pap smear was negligible (1 case per 4895 person-yrs of follow up)” “Duration of protection from a negative pap smear was greater with older age” 55-69yrs – q 5yr screening was strongly protective and annual screening had little advantage Same results were not seen in women 20-39yrs “Using Markov model after 3yrs of negative pap smears, comparing annual vs triennial screening would detect:” 3 more cases of cervical cancer per 100,000 women age 30-44 1 more case per 100,000 women age 45-59 No extra cases in women age 60-64

14. When should screening end? More controversy on when you should stop screening – should we be screening after the age of 65yrs? Highest mortality from cervical cancer seen in older women who have never been screened. Yet, it is rare to see high grade lesions in older women who have been screened Mortality increase after age 65, but benefit of screening declines with age

15. When should screening end? No current screening guidelines The decision is individualized Dependent on: Life expectancy Prior screening results HPV status Current sexual activity Generally, a women > 65yrs with 3 negative pap smears in the last 10 yrs, with no other risk factors needs no further screening

16. What if my patient had a hysterectomy? Small risk of cervical cancer in patients with prior hysterectomy in which cervix was taken out Certain groups at higher risk: Intact cervix post hysterectomy Hysterectomy done because of uterine or cervical cancer Exposure to DES in utero

17. So what are the recommendations? Cervical cancer screening guidelines from: USPSTF, ACS, ACOG Regarding what type of screening: ACS and ACOG allow liquid base cytology and/or routine HPV testing (for women >30yrs) USPSTF makes no recommendation on alternate screening tests due to insufficient evidence