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1. CERVICAL INTRAEPITHELIAL LESION PRESENTER: DR. HEM NATH SUBEDI RESIDENT OBGYN, COMS-TH , NEPAL

2. Contents Historical perspective Cervical anatomy Definition Classification Risk factors Epidemiology Etiology Screening Diagnosis Management

3. Cervical Anatomy The cervix is composed of Columnar epithelium: which lines the endocervical canal Squamous epithelium: which covers the exocervix . The point at which they meet is called the squamocolumnar junction (SCJ)

4. The Squamocolumnar Junction The SCJ rarely remains restricted to the external os . Instead, it is a dynamic point that changes in response to puberty, pregnancy, menopause, and hormonal stimulation. In neonates, the SCJ is located on the exocervix . At menarche, the production of estrogen causes the vaginal epithelium to fill with glycogen. Lactobacilli act on the glycogen to lower the pH, stimulating the subcolumnar reserve cells to undergo metaplasia .

5. Historical perspective The introduction of practical cytology by Papanicolau and Traut in 1943. In 1956 Reagan and Hamonic introduced the term dysplasia to designate these cervical epithelial abnormalities were characeteristized by cytologic atypia , increased mitotic activity and loss of polarity. Richart in 1976 proposed terminology of cervical intraepithelial Neoplasia (CIN) which combined the categories of severe dysplasia and carcinoma in situ in to term CIN3. National Cancer institute in Bethesda , maryland , the Bethesda system was introduced and first publised in 1991 and subsequently updated and revised in 2001.

6. Definition Cervical dysplasia is a cytological term used to describe cells resembling cancer cells. Cervical intraepithelial neoplasia (CIN) refers to histopathological description in which a part or full thickness of stratified squamous epithelium is replaced by cells showing varying degrees of dysplasia;however the basement membrane is intact.

7. Classification World Health Organization (WHO) In 1975 classified the CIN into three categories correlating with former grading of dysplasia and CIS. The grading is done according to the thickness occupied by the undifferentiated cells. CIN 1: Mild dysplasia CIN 2: moderate dysplasia CIN 3: Severe dysplasia and carcinoma in situ

8. The 2001 Bethesda System (Abridged) Epithelial Cell Abnormalities Squamous cell Atypical squamous cells (ASC) Of undetermined significance (ASC-US) Cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H) Low-grade squamous intraepithelial lesion (LSIL) Encompassing human papillomavirus /mild dysplasia/ cervical intraepithelial neoplasia (CIN) 1 High-grade squamous intraepithelial lesion (HSIL) Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2 and CIN 3 Squamous cell carcinoma

9. Glandular cell Atypical glandular cells (AGC) ( specify endocervical , endometrial, or not otherwise specified) Atypical glandular cells, favor neoplastic ( specify endocervical or not otherwise specified) Endocervical adenocarcinoma in situ (AIS) Adenocarcinoma

10. Comparison of Cytology Classification Systems Bethesda system Dysplasia/CIN System Papinicolau System With in normal limit Normal I Infection (organism should be specified) Inflammatory Atypia (Organism) II Reactive and non reactive changes Atypical squamous cell Of undetermined significance (ASC-US) Exclude high grade lesions (ASC-H) Squamous atypia HPV atypia , exclude LSIL Exclude HSIL HPV atypia IIR Low grade squamous intraepithelial lesion (LSIL) Mild dysplasia CIN 1 High Grade squamous intraepithelial lesionn (HSIL) Moderate dysplasia CIN 2 Severe dysplasia CIN 3 Carcinoma in situ III IV Squamous cell carcinoma Squamous cell carcinoma V

11. Epidemiology Five lakhs new cases of cervical cancer are reported annually. Incidence of cervical cancer in Nepal is 24.2 per 100,000. In India alone, 130,000 new cases occur with the death toll of 70,000 cases every year. Cancer of the cervix accounts for 15% of all cancers in women. Prevalence rate is 2.3 million annually globally. In India, it is 13–24 lakhs per year and 75% are in the advanced stages.

12. Etiology Human Papiloma Virus (HPV) +Other unidentified carcinogens.

13. Koilocytes These cells are often seen in young women suffering from HPV infection, and are cells with perinuclear halo in the cytoplasm. Koilocytes disappear as dysplasia advances.

14. Risk factors Average age 35–45 years. Pre-cancerous lesions occur 10–15 years earlier. Coitus before the age of 18 years. Multiple sexual partners. Delivery of the first baby before the age of 20 years. Multiparity with poor birth spacing between pregnancies. Poor personal hygiene. Carcinoma of the cervix shares similar epidemiological features to those of sexually transmitted diseases and viral infections and these are strongly linked to cancer cervix as causative agents. Poor socioeconomic status. Women not attending screening program. Immunodeficiency status like HIV.

15. Pathophysiology

16. Screening Screening for cervical cancer differs from other cancer screening because there is a well defined premalignant stage of disease which can be easily treated. Cervical screening was first introduced in British Columbia and Finland. It is now one of the most successful cancer prevention programmes .

17. Comparison for cervical screening program Guideline American cancer society ACOG Initial screening Age 21 or 3 yrs after vaginal sex Age 21 or 3 yrs after vaginal sex Interval Every year for conventional Every 2 yrs for liquid base pap Every 2-3 y after age 30 with 3 consecutive normals Every year for either liquid based Pap or conventional Every 2-3 y after age 30 with 3 consecutive normals Discontinue Age 70 if 3 consecutive normals in 10 yrs No upper limit of age

18. Methods of screening Cytology Conventional method(Pap Smear), The conventional Pap smear method had a sensitivity 51%, specificity 66.6%. Liquid based cytology (LBC) was developed to produce a more representative sample of the specimen than a conventional smear and to reduce contamination by blood cells, mucus and pus. Studies have been reported showing a wide range of sensitivities (44%-86%) and specificities (62%-98%). Sure path Thin prep.

19. Cervical cytology smear in CIN. This cytology preparation shows a clump of cervical epithelial cells demonstrating moderate and severe dyskaryosis . (From Figure 19.10. Alan Stevens, James Lowe and Ian Scott: Core Pathology, 3rd Ed. Elsevier, 2009.) Cervical squamous dysplasia, Pap smear (From Figure 13-25. Edward C. Klatt : Robbins and Cotran Atlas of Pathology, 2nd Ed. Saunders: Elsevier, 2010.)

20. Diagnosis Colposcopy Acetowhite Epithelium Epithelium that turns white after application of acetic acid (3%–5%) is called acetowhite epithelium. The application of acetic acid coagulates the proteins of the nucleus and cytoplasm and makes the proteins opaque and white.

21. Leukoplakia Translated literally, leukoplakia is white plaque. In colposcopic terminology, this plaque is white epithelium, visible before application of acetic acid. Leukoplakia is caused by a layer of keratin on the surface of the epithelium.

22. Punctation Dilated capillaries terminating on the surface appear from the ends as a collection of dots and are referred to as punctation . When these vessels occur in a well-demarcated area of acetowhite epithelium, they indicate an abnormal epithelium—most often CIN.

23. Mosaic Terminal capillaries surrounding roughly circular or polygonal-shaped blocks of acetowhite epithelium crowded together are called mosaic because their appearance is similar to mosaic tile These vessels form a “basket” around the blocks of abnormal epithelium. They may arise from a coalescence of many terminal punctate vessels or from the vessels that surround the cervical gland openings. Mosaicism tends to be associated with higher-grade lesions and CIN 2.

24. Atypical Vascular Pattern Atypical vascular patterns are characteristic of invasive cervical cancer and include looped vessels, branching vessels, and reticular vessels.

25. Endocervical Curettage ASCCP guidelines do not require endocervical curettage. In cases when an endocervical sample is needed, a cytobrush is sufficient for sampling the endocervical canal. Cervical Biopsy The cervical biopsy is performed at the area most likely to have dysplasia. If the lesion is large or multifocal, multiple biopsies may be necessary to ensure a complete sample of the affected tissue. VIA SCHILLER’S TEST: VILI DIRECT BIOPSY

26. HPV testing DNA based assays like digene Hybrid capture II,cervista HPV hr, cervista HPV 16/18 test, Cobas 4800 HPV .

27. COURSES OF CIN

28. Management

29. Treatment

30. Treatment modalities Cryotherapy Cryotherapy destroys the surface epithelium of the cervix by crystallizing the intracellular water, resulting in the eventual destruction of the cell. The temperature needed for effective destruction must be in the range of (–20° to –30°C). Nitrous oxide (–89°C) and carbon dioxide (–65°C) produce temperatures below this range and, therefore, are the most commonly used gases for this procedure. Cryotherapy should be considered acceptable therapy when the following criteria are met: CIN 1 that has persisted for 24 months, or CIN 2 Small lesion Ectocervical location only Negative endocervical sample No endocervical gland involvement on biopsy PHOTO

31. Cryotherapy probes with various size tips.

32. Laser Ablation Although rarely used in practice, laser ablation was used effectively for the treatment of CIN. The expense of the equipment combined with the necessity for special training limited the use of laser ablation. Most early CIN is now managed expectantly, so the need for ablation is decreasing.

33. Loop Electrosurgical Excision Loop excision should not be used before an intraepithelial lesion is identified with histopathology. Although “see and treat” may be appropriate in certain settings and among populations for whom follow-up is not possible, the potential excision of the entire transformation zone along with varying amounts of the cervical canal, may compromise birth outcomes. This is particularly true for young women, who may have large, immature transformation zones with extensive acetowhite areas.

34. Electrodes (Utah Medical, Midvale, UT) used for a loop electroexcision procedure. The width of the excised tissue specimens can range from 1.0 to 2.0 cm, and the specimen depth can be adjusted by sliding the guard attached to the electrode shaft. Following excision, the base of the cervix is often gently cauterized with a ball electrode.

35. Conization Conization is both a diagnostic and therapeutic procedure and has the advantage over ablative therapies of providing tissue for further evaluation to rule out invasive cancer Conization is indicated for diagnosis in women with HSIL or AGC , adenocarcinoma in situ and may be considered under the following conditions: Limits of the lesion cannot be visualized with colposcopy . The SCJ is not seen at colposcopy . Endocervical curettage (ECC) histologic findings are positive for CIN 2 or CIN 3. Substantial lack of correlation between cytology, biopsy, and colposcopy results. Microinvasion is suspected based on biopsy, colposcopy , or cytology results. The colposcopist is unable to rule out invasive cancer.

36. Hysterectomy Hysterectomy is considered a treatment of last resort for recurrent high-grade CIN. There are some situations in which hysterectomy remains a valid and appropriate (although not mandatory) method of treatment for CIN: Microinvasion CIN 3 at the endocervical limits of conization specimen in selected patients Poor compliance with follow-up Other gynecologic problems requiring hysterectomy, such as fibroids, prolapse , endometriosis, and pelvic inflammatory disease Histologically confirmed recurrent high-grade CIN.

37. Prevention Use of condoms Dietary changes Behaviour changes Human Papilloma Virus Vaccine Because HPV infection is a necessary factor in the development of cervical neoplasia , an important step in primary prevention was the development of a prophylactic vaccine to protect against HPV infection. Bivalent vaccine Quadrivalent Vaccine Nonavalent vaccine

38. Refferences Francisco Garcia. Intraepithelial Disease of the Cervix, Vagina, and Vulva: in Berek and Novaks Gynecology, 15 th edition, wolter and Kluwer . Newyork , pp 575. John A. rock. Precancerous lesions of Cervix: In Telindes textbook of operative gynecology,10 th edition, Wolter & Kluwer , Newyork,pp 1208-1225. VG Padubidri Shirish N Daftary.Cervical Intraepithelial Neoplasia , Carcinoma of Cervix: In Howkins & Bourne Shaw’s Textbook of Gynaecology 16 th edition, ELSEVIER , new delhi ,2011 pp485-490. Hiralal konor . premalignat lesions of cervix, vagina and vulva: In Dc Dutta’s text book of gynecology, jp , new delhi.2014 pp..

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