MANAGEMENT OF ABNORMAL PAP SMEAR DR ALIFAH BT MOHD ZIZI O&G SPECIALIST SGH

BETHESDA SYSTEM 2001 It was designed to provide uniform diagnostic language to facilitate communication between cytologists and clinician 3 general categories Within Normal Limits Benign Cellular Changes Epithelial Cell Abnormality

BETHESDA SYSTEM 2001 Adequacy of the sample is paramount 8000 – 12,000 squamous cells for conventional PS/10 HPF 5000 cells/10 HFP for liquid-based sample Presence of endocervical cells (at least 10) is recommended (not required for women < 40 y.o)

WHAT IS ABNORMAL PAP SMEAR? Abnormal due to inadequacy Abnormal due to inflammation Abnormal due to infection Abnormal due to dysplastic changes

1. INADEQUATE OR UNSATISFACTORY SMEAR

SATISFACTORY SPECIMEN.. Appropriate labeling and identifying information Relevant clinical information Adequate numbers of well preserved and well visualized squamous epithelial cells. An adequate endocervical / transformation zone component (from a patient with a cervix). Quality of the Pap smear will still be noted when: 1. More than 10 well preserved endocervical or metaplatic cells are seen 2. No blood or inflammation obscuring the Pap smear

INADEQUATE/UNSATISFACTORY SMEAR A smear that is unreliable for the detection of cervical epithelial cell abnormalities

INADEQUATE/ UNSATISFACTORY SMEAR 1. Sampling Scanty cells Blood, mucous, pus 2.Preparation Too thick due to poor spreading Air drying artifact Broken slide 3.Mainly endocervical cell

HOW TO DEAL WITH INADEQUATE/ UNSATISFACTORY SMEAR ?? Correct timing of smear Do not use cream or gel Cleaning of excessive mucus Choice of sampling devices Correct spreading Rapid fixation (< 10 second) Do use cream or gel

GIVE A COURSE OF ESTROGEN IF POST MENOPAUSE WITH ATROPHY PAP SMEAR UNSATISFACTORY TX ANY INFECTION GIVE A COURSE OF ESTROGEN IF POST MENOPAUSE WITH ATROPHY REPEAT 6/12 NEGATIVE FOR INTRAEPITHELIAL LESSION 2ND SMEAR UNSATISFACTORY REPEAT 6/12 3RD SMEAR UNSATISFACTORY ROUTINE SCREENING COLPOSCOPY

2. INFLAMMATORY SMEAR

Inflammation on Pap smear results, does not indicate any particular pathology Therefore, does not necessitate routine treatment.

POSSIBLE CAUSES…… Infection Chronic cervicitis Atrophic cervicitis Chemical or mechanical irritation to cervix- tampoon, douching

NEGATIVE FOR MALIGNANT CELL PAP SMEAR NEGATIVE FOR MALIGNANT CELL INFLAMMATORY TX ANY INFECTION OR ATROPHY REPEAT 6/12 NORMAL 2ND SMEAR INFLAMMATORY REPEAT 6/12 ROUTINE SCREENING 3RD SMEAR INFLAMMATORY COLPOSCOPY

3. ABNORMAL SMEAR DUE TO INFECTION

COMMON INFECTIONS…. Tricomonas vaginalis Fungal ie candidiasis Bacterial Vaginosis Actinomyces Herpes Simplex ORGANISM TREATMENT TRICHOMONAS VAGINALIS T. METRONIDAZOLE 400MG TDS FUNGAL INFECTION (CANDIDA) CANNESTAN PESSARY 200MG ON BACTERIA VAGINOSIS

NEGATIVE FOR MALIGNANT CELL PAP SMEAR NEGATIVE FOR MALIGNANT CELL SPECIFIC MICROORGANISM TREAT ANY INFECTION REPEAT PAP SMEAR 6/12 NORMAL ROUTINE SCREENING

4. ABNORMAL SMEAR DUE TO DYSPLASTIC CHANGES

SQUAMOUS CELL ABNORMALITY GLANDULAR ABNORMALITY DYSPLASTIC CHANGES SQUAMOUS CELL ABNORMALITY GLANDULAR ABNORMALITY AGS AIS INVASIVE ADENOCARCINOMA ASCUS ASC-H LGSIL HGSIL INVASIVE SQUAMOUS CELL CARCINOMA

Spectrum of Changes in Cervical Squamous Epithelium Caused by HPV Infection CIN* 1 CIN 2 / CIN 3 / Cervical Cancer Normal Cervix Key Point Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types1 and is linked to the activity of E6 and E7 proteins.2 Background In benign HPV-associated skin lesions, the HPV virus maintains its genome as episomes at low copy numbers (10–200 copies/cell) in the basal cells of the epithelium separate from the host cell DNA. To maintain its viral DNA as an episome, viral E1 and E2 proteins are expressed. Failure to express E1 leads to the integration of the HPV genome into the host cell chromosome.3 Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types1 and is considered an important step in tumor progression.2 In malignant HPV-associated skin lesions, HPV DNA integration into the host cell’s chromosome regularly occurs through a break in the viral genome around the E1/E2 region. Integration-mediated disruption of E2 may trigger uncontrolled expression of E6 and E7, resulting in cellular transformation.2 The E6 protein associates with the tumor suppressor protein p53 and promotes proteolytic destruction of the protein. This leads to malignant transformation and loss of regulated cell growth. The E7 protein associates with the retinoblastoma protein (pRB), which inactivates the cell cycle restriction function of this protein.2 References 1. Gallo G, Bibbo M, Bagella L, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol. 2003;56:532–536. 2. Syrjänen KJ, Syrjänen SM. Molecular biology of papillomaviruses. In: Papillomavirus Infections in Human Pathology. Chichester, United Kingdom: John Wiley & Sons, Inc.; 2000:11–51. 3. Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32(suppl):S7–S15. *CIN = cervical intraepithelial neoplasia Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.

NATURAL HISTORY…….. % Regress Persist Progress to CIS Progress to Invasion CIN 1 60 30 10 1 CIN 2 40 35 20 5 CIN 3 <56 - 18 (5y), 36(10y)

SQUAMOUS CELL ABNORMALITY…

ABNORMAL PAP SMEAR DUE TO DYSPLASTIC CHANGES – SQUAMOUS CELL ABNORMALITIES 1. Atypical Squamous Cells (ASC) Atypical Squamous Cells-Undetermined Significance (ASC-US) Atypical Squamous Cells, Cannot Exclude High Grade Lesion (ASC-H) 2. Low-grade Squamous Intraepithelial Lesion (LSIL) (Mild Dyskaryosis / HPV/CIN 1) 3. High-grade Squamous Intraepithelial Lesion (HSIL) (Mod or Severe Dyskaryosis / CIN 2,3) 4. Invasive Squamous Cell Carcinoma

1.ATYPICAL SQUAMOUS CELL (ACS) 1. Undetermined Significance (ASC-US) Cytologic changes suggestive of a low grade squamous lesion but lack criteria for definitive interpretation. 2. Cannot Exclude High Grade Lesion (ASC-H) Cytologic changes suggestive of a high grade squamous lesion but lack criteria for definitive interpretation.

ATYPICAL SQUAMOUS CELL (ASC) PAP SMEAR ATYPICAL SQUAMOUS CELL (ASC) ASCUS HPV DNA TESTING POSITIVE NEGATIVE REPEAT 6/12 COLPOSCOPY NEGATIVE FOR INTRAEPITHELIAL LESSION RESUME NORMAL SCREENING

PAP SMEAR ASC-H COLPOSCOPY

2. LOW GRADE INTRAEPITHELIAL LESSION (LGSIL) / CIN 1 CIN I being the morphologic manifestation of a self-limited sexually transmitted HPV infection 60% of CIN I regress spontaneously 30% of CIN I persists. 10% of CIN I lesions progress to CIN III, 1% may ultimately progress to invasive cancer.

NILM LSIL Immediate colposcopy Colposcopy No yes Assessment of client = No yes Assessment of client Presence of at least 1 criteria: -Age > 30 yrs Poor compliance Immunocompromised Sx Hx of pre-invasive lesion +ve for high risk HPV (16,18,31,33,45,52,58) Repeat smear in 6/12 60% NILM LSIL Immediate colposcopy Resume routine screening schedule Colposcopy

MANAGEMENT APPROACH A lesion that persist after 1-2 years or any progression during follow up suggest need of treatment If HPV testing is available, +ve HPV: indication for treatment - Treatment- local ablative/ excission -Follow up after treatment for CIN1 -repeat smear in 6/12 -repeat smear and colposcopy in 12/12 -If normal, yearly pap smear x 2 years then back to normal routine

3.HIGH GRADE INTRAEPITHELIAL LESSION (HGSIL)/ CIN 2-3 CIN 2-3 is a cervical cancer precursor 1.CIN 2 40% of CIN II regress 30% of CIN II persist 20% of CIN II progress to CIN III 5% of CIN II progress to CIN III 2. CIN 3 33% of CIN III regress 18% of CIN III progress to invasive disease over a 10 years 36% of CIN III progress to invasive disease over a 20 years

Subsequent management depends on: Whether lesion identified PAP SMEAR HGSIL COLPOSCOPY AND BIOPSY Subsequent management depends on: Whether lesion identified Whether colposcopy satisfactory Annual smear following treatment

MANAGEMENT APPROACH EXCISION METHOD LLETZ Cold knife cone biopsy Hysterectomy

ABLATIVE METHODS Cryocautery Electrodiathermy Cold coagulation

4. INVASIVE SQUAMOUS CELL CANCER PAP SMEAR INVASIVE SQUAMOUS CANCER COLPOSCOPY AND BIOPSY Subsequent management depends on: Stage of the disease

GLANDULAR ABNORMALITY

ABNORMAL PAP SMEAR DUE TO DYSPLASTIC CHANGES- GLANDULAR CELL ABNORMALITIES 1.Atypical Glandular Cells (AGS) (undetermined or favour neoplastic) 2.Adenocarcinoma in Situ (AIS) 3. Invasive Adenocarcinoma

GLANDULAR ABNORMALITIES The most common significant lesions associated with AGC (Atypical Glandular Cells) are actually squamous Management should include colposcopy and endocervical sampling

ATYPICAL ENDOMETRIAL CELLS Always perform endometrial sampling If endometrial sampling is negative : colposcopy with endocervical sampling

GLANDULAR ABNORMALITIES

OTHERS…

LOCAL ESTROGEN CREAM 1G ON FOR 2 WEEKS THEN TWICE WEEKLY FOR 6 WEEKS ATROPHY SMEAR PAP SMEAR ATROPHY LOCAL ESTROGEN CREAM 1G ON FOR 2 WEEKS THEN TWICE WEEKLY FOR 6 WEEKS REPEAT IN 6 MONTHS

REACTIVE CELLULAR CHANGES PAP SMEAR REACTIVE CELLULAR CHANGES DUE TO RADIATION, REPAIR OR IUCD REPEAT IN 1 YEAR

ABNORMAL PAP SMEAR IN PREGNANCY Reported abnormal smear during pregnancy 1%- 8% Follow-up should be similar to non pregnant state-every trimester Regardless of gestation, suspicious lesion should be biopsied. Cervical biopsy does not increase the risk of miscarriage If evidence of invasive cancer- require excission

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