Management of the Abnormal Pap Smear Joyce King, FNP, CNM, PhD Disclosure • “I have no real or perceived vested interests that relate to this presentation nor do I have any relationships with pharmaceutical companies, biomedical device manufacturers, and/or other corporations whose products or services are related to pertinent therapeutic areas.” Objectives • Discuss the epidemiology of cervical disease. • Discuss the physiology of the normal cervix. • Describe the correct techniques for Pap smear testing. • Understand the Bethesda system of reporting Pap smear results. • Review current guidelines for management of abnormal results. Cervical Cancer - Epidemiology • Estimated 11,070 new cases of invasive cervical cancer are expected to be diagnosed in 2008. • Estimated 3,870 deaths from cervical cancer during this same time period. • Most cases are found in women younger than age 50. • Risk is highest in Hispanic women and African -American women. Risk Factors for Cervical Cancer • HPV infection – factors that promote infection to progress to cancer – – – – – Immunosuppression High parity Cigarette smoking Long-term use of oral contraceptives Nutritional factors • Women who begin having sex at an early age. • Multiple sexual partners. Human Papilloma Virus • > 100 types • Sexually transmitted infection • High-risk types - 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82 – Based on oncogenic potential High-Risk HPV Infection • 80% of infected women clear the virus in 6-8 months • 20% develop cervical dysplasia – 80% virus clears – 20% infection persists How Dies HPV Cause Cervical Cancer? • High-risk HPV exerts oncogenic activity through the oncoproteins E6 and E7. • These oncoproteins bind to tumor suppressor gene products. • This interaction leads to DNA changes and genetic instability, allowing oncogenic alterations. How Dies HPV Cause Cervical Cancer? • The length of time between initial infection and invasive cervical cancer is estimated to be 10-15 years • This length of time suggests that the development of cancer requires changes in the genome of HPV infected cells. • Low and intermediate risk HPV have been found in abnormal Pap smears, but not in invasive cancers. Signs and Symptoms of Cervical Cancer • Abnormal vaginal bleeding – Between menses. – After sexual intercourse, douching, or a pelvic exam. – Menstrual bleeding may last longer and be heavier than usual. – Bleeding after menopause • Increased vaginal discharge • Pain with intercourse Prevention of Cervical Cancer • Monogamy • Condoms • HPV Vaccine (Gardisil®) – Highly immunogenic for HPV 6, 11, 16, 18 – Recommended for all girls and young women between 9 and 26 years-of-age The Normal Cervix Physiology of the Cervix • Types of cells – Columnar – Line the endocervix – Squamous – Line the ectocervix and vagina Squamocolumnar Junction (SJC) • Original- border where original squamous cells meet columnar cells. • Present- innermost border where maturing squamous cells meet native columnar cells. Transformation Zone • Area of actively maturing epithelium between present SCJ and original SCJ – 90% of neoplasias occur in this area Original Squamous Epithelium Exocervix Transformation Zone Columnar Epithelium Squamous Metaplasia Original Squamocolumnar Junction Present Squamocolumnar Junction Endocervix Squamous Metaplasia • Normally occurring transition of columnar cells to squamous epithelium – Due to lowered vaginal pH in response to increased estrogen – Process occurs in transformation zone Puberty Reproductive Years Menopause The Pap Smear Pap Smear • Historically, cytologic evaluation of cervical and vaginal cells was first proposed by Dr. Papanicolaou in the 1940’s, as a method of detecting cervical cancer and precursors. • This evaluation has proved to be the most cost effective method of cancer screening of the cervix to date. The Benefit of the Pap Test • Since the introduction of the Pap smear, there has been a substantial decrease in the incidence of invasive cervical cancer as well as death from cervical cancer. ACS Recommendations for Pap Smear Screening • Begin at age 21 or three years after initiating sexual activity. • Annual pap smears - Ages 21-30 (with liquid-based cytology, testing can be every 2 years). • Beginning at age 30 – with 3 normal Pap test in a row, may be tested every 2 to 3 years, OR ACS Recommendations for Pap Smear Screening • Test every 3 years with either the regular Pap test or liquid-based Pap test, plus the HPV DNA test. • Women 70 years of age and older may choose to stop having Pap testing – 3 or more normal Pap tests in a row – No abnormal Pap test results in the last 10 years ACS Recommendations for Pap Smear Screening • Women with a total hysterectomy due to benign causes do not need Pap testing. • Women with a simple hysterectomy (still have cervix) need to follow the above guidelines. Epidemiology of Abnormal Pap Tests • More than 50 million Pap tests each year in the US • 5% of all pap smears are abnormal • More than 95% of all cervical cancers exhibit evidence of HPV J. Natl. Cancer Inst. 2008 100:841; doi:10.1093/jnci/djn192 Sampling Technique – Endocervical canal – Exocervical Transformation Zone Guidelines for Obtaining • Use largest speculum that allows for good visualization but is comfortable. • Inspect cervix for abnormalities • Use the contoured end of the spatula and rotate 360 degrees while maintaining firm contact • Insert cervical brush into os and rotate 90 - 180 degrees, OR • Use brush designed to retrieve both types of cells and rotate 360 degrees Pitfalls in Cervical Cytology – Patient-related • Recent douching • Recent sexual intercourse • Heavy discharge, blood or vaginal creams • Lack of follow-up of abnormal findings Pitfalls in Cervical Cytology – Practitioner-related • Inappropriate sampling • Inadequate endocervical cells • Too thickly spread on slide • Delay in fixation • Screening errors • Lack of follow-up Pitfalls in Cervical Cytology – Lab-related • Confusing terminology • Missed diagnosis – False positive – False negative Improvements in Testing • Liquid-based smears • Rescreening strategies - computerized devices (AutoPap®) • HPV DNA testing Bethesda System of Reporting • The Bethesda System (TBS) of reporting Pap smear results was developed in 1988, and revised in 1998 and 2001. • The purpose was to standardize cervical and vaginal cytopathologic reporting and to facilitate communication between clinicians and cytopathologists. Bethesda 2001 Terminology • Specimen Adequacy – Satisfactory for evaluation • Unsatisfactory for evaluation – Specimen rejected/not processed – Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because (specify reason) Bethesda System of Reporting • General categories – Negative for intraepithelial lesions or malignancy – Epithelial cell abnormalities – Other malignant neoplasms Epithelial Cell Abnormalities • Atypical squamous cells – – of undetermined significance (ASC-US) • Infection • Irritation • Precancer – cannot exclude HSIL (ASC-H) Epithelial Cell Abnormalities • Low grade squamous intraepithelial lesion (LSIL) – Encompassing mild dysplasia/CIN1(cervical intraepithelial neoplasia) • High grade squamous intraepithelial lesion (HSIL) – Encompassing moderate and severe dysplasia, CIN 2,3 • Squamous cell carcinoma Natural History of Cervical Dysplasias • Approximately 66% of ASC-US will resolve spontaneously • Approximately 50% of LSIL will resolve spontaneously • Approximately 33% of HSIL will resolve spontaneously • Of those that regress, most will do so in 6 months HPV DNA Test • Does not replace the Pap test • Not recommended for a screening test in women under 30 • Used in women of any age who have slightly abnormal Pap test results – Low-risk HPV – High-risk HPV Other Tests Used with Abnormal Cervical Cytology • Colposcopy • Cervical biopsies – – – – Colposcopic biopsy Endocervical curettage Cone biposy LEEP Case #1 B.S. is a 21 y.o. 0030 that presented to your clinic for a Pap test one week ago. Her results indicated ASCUS. How should this result be managed? Management of ASC-US (age >20 ) • HPV DNA testing preferred if liquid based sampling – HPV + - Colposcopy – HPV - - Repeat cytology in 12 months • Repeat cytology at 6 and 12 months – Both test negative – routine screening – Continues with ASC – colposcopy • Colposcopy Management of ASC-US (age >20 ) • Colposcopy – No CIN • HPV unknown – repeat Pap in 12 months • HPV postive – repeat Pap in 6 & 12 months with HPV DNA testing at 12 months – CIN – Manage per ASCCP (American Society for Colposcopy and Cervical Pathology Guideline) Management of ASC-US or LSIL (age <20 ) • Repeat cytology at 12 months – ≥ HSIL – Colposcopy – ≤ HSIL – Repeat cytology in 12 months • ≥ ASC - Colposcopy Management of ASC-H • Colposcopy and biopsy – No CIN 2,3 • Cytology at 6 & 12 months • HPV DNA testing at 12 months Management of LSIL (age >20) • Colposcopy and endocervical sampling – No CIN 2,3 • Cytology at 6 & 12 months • HPV DNA testing at 12 months Case #2 S.J., a 37 year old 5026 presents for her GYN exam. Her last exam was 7 years ago. She complains of postcoital spotting during the previous 2 months. Her past history reveals that her first sexual exposures was at 16 and that she has had 7 lifetime partners. Her Pap smear showed HSIL. How should this patient be managed? Management of HSIL (age >20) • Immediate loop electrosurgical excision OR • Colposcopy – No CIN 2,3 – Unsatisfactory colposcopy – diagnostic excisional procedure – Satisfactory colposcopy • Observation with colposcopy & cytology at 6 month intervals for 1 year • Diagnostic excisional procedure • Review material Management of HSIL (age < 20) • Colposcopy – Satisfactory exam and no CIN 2,3 – Observation with colposcopy & cytology at 6 months intervals for up to 2 years • HSIL persists for 1 year – biopsy, if no CIN 2,3, continue observation • HSIL persists for 24 months with no CIN 2,3 identified – diagnostic excisional procedure Management in Pregnancy • Only indication for treatment is if invasive carcinoma is present • Defer colposcopy for those pregnant women at low risk for having cancer Treatment for Dysplasias • Cryotherapy • Laser ablation • Loop electrosurgical excision procedure (LEEP) Cryotherapy • Indications – – – – – CIN 1,2 Small lesion Ectocervical location Negative ECC No endocervical glad involvement Cryotherapy • Advantages – Reliability – Ease of use – Low cost • Disadvantages – Inability to tailor to lesion size – No pathologic specimen Laser Ablation • Indications – – – – – CIN 1-3 Large lesions Irregular cervix Vaginal extension of dysplasia Satellite lesions Laser Ablation • Advantages – Reliability – Can be tailored to lesion size – Rapid healing • Disadvantages – Expensive equipment/training – Complications (e.g. burns) – No pathologic specimen LEEP (Loop Electrosurgical Excision Procedure) • Indications – – – – CIN 1-3 Unsatisfactory colposcopy Positive ECC Significant discrepancy between cytology and histology – Suspicion of invasion – Glandular dysplasia LEEP • Advantages – Reliability – Ease of use – Can be tailored to lesion size – Produces pathologic specimen • Disadvantages – High cost Epithelial Cell Abnormality Glandular Cells • Atypical glandular cells – Endocervical – Endometrial – Cervical glandular cells Note: The AGC lesions are associated with much greater risk for cervical neoplasia than ASC or LSIL Epithelial Cell Abnormality Glandular Cells • Adenocarcinoma in situ – Precursor of invasive cervical adenocarcinoma – Always evaluated by diagnostic excisional procedures – If fertility is undesired – hysterectomy is recommended Treatment of Abnormal Glandular Cells • All abnormal glandular cells get colposcopy and HPV DNA testing and endometrial sampling (if >35 years or at risk for endometrial neoplasia), EXCEPT • If atypical endometrial cells are present on the Pap test. This indicates endometrial and endocervical sampling; if no abnormal endometrial pathology then colposcopy. Future Screening Methods • Fluorescence spectroscopy • Polar probe • Molecular markers Treatment for Cervical Cancer • Staging • Surgery – – – – – – Cryosurgery Laser surgery LEEP Cold knife conization Hysterectomy Radical trachelectomy • Radiation • Chemotherapy Summary • Cervical disease is predominately a sexually transmitted disease. • Adequate retrieval and preparation of cells is imperative. • Regular Pap smears does reduce the incidence of invasive cervical cancer. • HPV testing is important and helps to guide the management of abnormal Pap tests. Summary cont’d • Treatment of abnormal Pap smears is based on risk factors and degree of severity of the lesions. • New screening techniques are on the horizon. • Vaccine for prevention is here and should be encouraged.