Cervical Dysplasia and Faculty Invasive Cervical Cancer Satellite Conference and Live Webcast Friday, October 10, 2008 Michael A. Finan, M.D., F.A.C.S. 1:00 - 3:00 p.m. Chief, Gynecologic Oncology Produced by the Alabama Department of Public Health Video Communications and Distance Learning Division Objectives Objectives • Overview of cervical cancer • Understand staging of cervical cancer • Understand Role of HPV • Describe treatment of various stages of • Apply algorithms from www.asccp.org cervical cancer • Apply methods of diagnosis of cervical • Understand roles of surgery, radiation cancer therapy and chemotherapy for the management of cervical cancer 1 Cervical Dysplasia Epidemiology • Schauenstein (1908) first proposed that SCC • Abnormal Pap = 3.5 million per year (7%) of cervix evolves by a progression of a • CIS = 50,000 per year preinvasive lesion (carcinoma in situ) • CXCA = 13,000 per year – 4,500 deaths per year • Overall incidence: 8.7/100,000 women Papanicolaou described CIS and less • • Second most common female cancer anaplastic lesions called dysplasia worldwide • Among top 5 causes cancer death in developing countries (20-30% of female • WHO defines dysplasia as “lesion in which cancers) part of the epithelium is replaced by cells – Pap decreased cancer by 50% in showing varying degrees of atypia.” U.S.! Risk Factors • Age first intercourse • Low • Multiple partners (>2) socioeconomic status • STD > 3 years pap • HPV • High risk partner • High risk HPV • Other • Immunosuppression • • Smoking – Contraceptive hormones – Radiation HPV Human Papilloma Virus • Non-enveloped DNA encased in capsid > 80 subtypes (31 anogenital) • E2 transcriptional regulation of HPV • HPV stronger association with cancer genes E2 E5 Integration Epidemic past 20 yrs disrupts E2 • E4 leading to L2 • HPV DNA found > 95% of SCC E1 increased E6/E7 Late genes encode capsid HPV-16 transcription • Not only factor proteins E7 L1 E7 binds pRb • 43% college women HPV+ (but <5% E6 LCR CIN) E6 binds p53 2 HPV Types Cervical Dysplasia Schematic High Risk HPV Testing Low Risk Intermediate High Outer 1/3 Risk Risk 31, 33, 35, Middle 1/3 6, 11, 26, 39, 51, 52, 16, 18, 42, 44, 54, Inner 1/3 55, 58, 59, 45, 56 70, 73 66, 68 • Low Risk: never found alone in invasive cancer • HPV-16: more common in squamous lesions • HPV-18: more common in endocervical lesions “In The Zone” Understanding The Cervical • Cervix mullerian duct origin Transformation Zone • Lined by columnar epithelium E2 • 18-20 wks. gestation colonized by squamous epithelium E2 • Squamocolumnar Junction = Transformation Zone E2 • Zone changes position depending on hormonal influence From: Practical Gynecologic Oncology 3rd Ed. Berek & Hacker Screening Is Good Bethesda 2001 • Cervical cancer #1 in incidence & • Specimen type mortality in women prior to 20th century • Specimen Adequacy • Screening for premalignant lesions – Satisfactory knocked it down to #2 worldwide – Unsatisfactory due to… (yipee) • General Categorization • Dichotomy b/t developing & developed – Negative, Epithelial cell abnormality, countries other • “Preventable disease” 3 Bethesda 2001 Bethesda 2001 • Interpretation and Result • Squamous Cell – Negative for Intraepithelial Lesion or – Atypical Squamous Cells Malignancy • ASC-US • Organisms • ASC-H –Trich, Candida, BV, HSV, etc – LSIL (HPV, mild dysplasia) • Other – HSIL –Reactive inflammation, IUD, • Moderate dysplasia radiation, Atrophy • Severe dysplasia Bethesda 2001 Bethesda 2001 Abnormalities • Squamous Cell • Squamous Cell – Squamous Cell Carcinoma – Atypical Squamous Cells ASC-US • Glandular Cell • • ASC-H (can’t r/o high grade lesion) – Atypical Endocervical, Endometrial, – LSIL (HPV, mild dysplasia) Glandular cells – HSIL AG-NOS • • Moderate dysplasia • AG-favor neoplasia • Severe dysplasia – Adenocarcinoma – Squamous Cell Carcinoma Bethesda 2001 Abnormalities Dysplasia Natural History • Glandular Cell Progress Progress Biopsy Regress Persist to – Atypical Endocervical, Endometrial, to CIN 3 Cancer Glandular cells CIN1 57% 32% 11% <1% • AG-NOS • AG-favor neoplasia CIN2 43% 35% 22% 5% – Adenocarcinoma CIN3 32% 56% N/A 12% Ostor AG. Int J Gyn Path. 1993 4 Infectious Or Neoplastic? Bottom Line Normal Infection Neoplasia Differentiate • No Neoplasia • Infection (HPV) • Neoplasia • No Infection • No Neoplasia • Infection normal from infectious Pap Normal Normal ASCUS ASCUS ASCUS LSIL and LSIL LSIL HSIL HSIL infectious from neoplastic Colposcopy The Colposcope • Adequacy? – visualize entire TZ and entire lesion (if any) • Visualize with Green filter- atypical vascularity • 3-5% acetic acid solution – Dries cells, neoplastic cells with higher nuclear:cytoplasmic ratio Colposcopy Colposcopy • Lugol’s Solution (1/4 strength)- Shiller’s Test • Endocervical Curettage (ECC) – Taken up by glycogen containing normal – Identify dysplasia within endocervical epithelium canal – Not taken up by atrophic or neoplastic – Controversial epithelium or columnar epithelium – Some studies show cytobrush sampling more sensitive although less specific 5 Colposcopic Findings Normal? Acetowhite Acetowhite • Acetowhite Changes – Increased N:C ratio – Abnormal intracellular keratins – Intracellular dehydration Before Acetic Acid After Acetic Acid Colposcopic Findings Punctation And Mosaicism • Abnormal vascularity Punctation Mosaicism – Punctation and Mosaicism • HPV capillary proliferative effect • Intraepithelial pressure created by expanding neoplastic tissue • Tumor angiogenesis factor – Atypical blood vessels • Margins Rolled, peeling edges or internal – • Epithelial proliferation squeezes demarcation between areas of differing appearance are abnormal capillaries up to surface Where’s the Dysplasia? Abnormal Vascularity Punctation Coarse Mosaicism & Punctation 6 Colposcopic Warning Colposcopic Warning Signs Of Invasion Signs Of Invasion • Friable epithelium with contact • Extremely abnormal punctation and bleeding mosaicism • Irregular surface contour • High grade lesions occupying 3 or 4 quadrants • Surface ulceration or erosion • High grade lesions extending into canal • Atypical blood vessels either >5mm or beyond colposcopic view Lugol’s Tischler Biopsy Instrument Is this Normal? Nabothian Cyst Cancer Lugol’s Iodine Application Interventional Techniques Biopsy Diagram • Excision – Cold Knife Cone – Loop Electrosurgical Excision Procedure (LEEP, LLETZ, LOOP) – Laser Cone • Ablation – Cyrotherapy – Laser vaporization therapy 7 Cold Knife Cone Cold Knife Cone • Lugol’s to delineate lesion • Tag 12 o’clock for orientation • Stay sutures at 3 and 9 o’clock for • +/- ECC or D&C traction & hemostasis • Cauterize base • Intracervical vasopressin for – Sturmdorf sutures not advisable hemostasis because of risk of burying residual • Sound endocervical canal to guide disease excision • Conical excision with #11 blade LEEP Cold Knife Cone Illustration • Visualize cervix with non-conductive speculum with suction attachment • Lugol’s to define lesion • Paracervical and intracervical block with Lidocaine • 35-55W or either cutting or blend LEEP LEEP Diagram • Excise area 7-10mm deep at center – Maximum depth of involved glands 5.2mm • Ball electrode cautery to base and periphery with coag current • +/- ECC • Monsel’s as needed for hemostasis 8 ASC-H Slide HPV Testing- ALTS Side Effects Of LEEP LSIL Algorithm Distribution • Bleeding (now & later) All Paps Pap normal ≥ ASCUS • Infection 92% 8% CIN2+ 15% • Damage to adjacent organs HSIL LSIL ASCUS 0.5% 2% 5% • Cervical incompetence High risk High risk High risk • Cervical stenosis HPV pos CIN2+ HPV pos HPV pos 25% 97%* 89% 53% HPV Triage reduces *Missing or false neg values Colpo of ASCUS by 50% ASC-US Summary ASC-US Algorithm • If using Thin Prep/HPV testing – ASC-US HPV test and colpo if (+) • If (-) then repeat HPV test only in 1 yr. (or repeat Pap) – >ASC-US Colpo • If not using ThinPrep/HPV – Colpo for ASC-US*2 – If ASC-H or greater Colpo See www.asccp.org Atypical Glandular Cells of Undetermined Significance AGUS Algorithm (AGUS) • Where are glandular cells? • Endometrium • Endocervix 9 AGUS Mgmt of AGUS HSIL AGUS Difficult to differentiate HSIL from AGUS on Pap Significance Of AGUS AGUS Summary High Any HSIL • Colpo with ECC for everyone Grade Pap (including Glandular squamous) Lesion • Endometrial Bx if >35 or history of AGUS 5-39% 1-8% Reactive irregular bleeding (suspicion of AGUS NOS 9-41% 0-15% endometrial hyperplasia or CA) AGUS favor 27-96% 10-93% neoplasia See www.asccp.org Special Circumstances- ASC-US Adolescent Postmenopausal • Vaginal atrophy causes cells to resemble HSIL or ASCUS – Predominance of smaller basal cells • If atrophy present, treat with vaginal Estrogen for 6 weeks and re-evaluate See www.asccp.org 10 ASC-H ASC-High Grade • ASC- Can’t rule out high grade All Paps lesion – 87% High-risk Pap normal ≥ ASCUS HPV positive 92% 8% – 30% CIN2 or CIN3 on CIN biopsy HSIL LSIL ASCUS 2+ 0.5% 2% 5% 15% • Immediate HPV HPV HPV CIN pos pos Colposcopy pos 2+ 97%* 89% 53% 25% See www.asccp.org LSIL HSIL- “See & Treat” • HSIL Severe Dysplasia (in multiparous All Paps • Almost all women) High Risk – Who doesn’t get LEEP? HPV positive Pap normal ≥ ASCUS – HPV 92% 8% – If negative or CIN1 on colpo- where’s testing CIN the HSIL coming from? useless HSIL LSIL ASCUS 2+ 0.5% 2% 5% 15% • LEEP for diagnosis (not if • 30% CIN2/3 nulliparous) • Immediate – If CIN2/3 on colpo then LEEP for HPV HPV HPV Colpo pos CIN2 treatment pos pos + 97%* • Management may differ in 89% 53% 25% See www.asccp.org See www.asccp.org pregnancy, adolescence