MANAGEMENT OF CIN: Seminar

Introduction The concept of preinvasive disease, carcinoma cervix precusors dated at the late 19th century. CIS was described in 1932 by Broders. The association between CIS with invasive cervical cancer was subsequently reported. Invasive carcinoma of cervix are lately preceeded by a long phase of preinvasive disease. In 1956, Reagan and Hamonic introduced the term dysplasia. Dysplasia : cervical epithelial abnormalities that were characterized by cytologic atypia, increase mitotic activity, loss of polarity.

 Mild dysplasia- when these abnormality involves

lower one third of squamous epithelium. Moderate dysplasia- involvement of middle third. Severe dysplasia- involvement of upper one third of the epithelial layer. Carcinoma in situ- a full thickness change is called carcinoma in situ. In 1976 Richart introduced the terminology of cervical intraepithelial neoplasia (CIN). A cytologic and histologic classification of preinvasive cervical atypia or neoplastic change. CIN 1- mild dysplasia CIN 2- Moderate dysplasia CIN 3- severe dysplasia / carcinoma in situ

The changing terminology of cervical cytology (HPE) (Cytology) Dysplasia CIN Bethesda HPV change LSIL Mild displasia CIN I Moderate displasia CIN II Severe dysplasia CIN III HSIL Carcinoma in situ

 Annually, an additional 1,250,000 American women are diagnosed with precancers by cytology using the Papanicolaou (Pap) smear. American Cancer Society, 2005 Up to 7 millions worldwide may have precancerous condition that need to be identified and treated. ACS8 Precancerous lesion of cervix -26000-45000
Nepal cervical cancer prevention situation Analysis, 2008 Retrospective study of 880 conventional PAP smear in dep.of pathology in chitwan medical college,Nepal (June 2009 to November 2010.) Abnormal cytology- 11 HSIL 40% LSIL 20% ASC-US 13% AGC 13% Age group- 20-80 (average 36.7 yrs) above 40 yrs 80% (Journal of Pathology of Nepal (2011) Vol. 1,30-33)

 Transformation zone is the site for the displasia. Common site - anterior lip of cervix. Progress horizontally to involve the entire transformation zone. CIN is most common during menarche and pregnancy when metaplasia is most active.

Risk factors
STD Chlamydia, gonorrhea, mycoplasma HPV (16, 18,31) Early age at first sexual intercourse Early age at first pregnancy Multiple sexual partners Low socioeconomic status Cigarette smoking Immunocompormised OCP

Human papilloma virus

DNA virus of papovaridae family. High-risk types 16, 18,31,33,35,39. Cytologic change- koilocyte first recognized by Koss and Durfee in1956. HPV DNA positivity strongly correlate with increasing numbers of sexual partners. HPV DNA positive- 40% abnormal PAP test. Invasive cervical cancer associates with 50% - HPV 16 12% - HPV 18 In Nepal a pilot study done by NHRC, HPV 16 is more common than 18.

 HPV associated with low grade CIN. 90% of CIN attributed to HPV infections. HPV DNA detect 88% high grade lesion. Screening CIN has no symptom, so it is essential to women to have regular cervical screening to detect any early change. Aim of screening is to reduce - Incidence of cervical cancer - Mortality from cervical cancer

Screening methods Cervical cytology( PAP test) - Conventional - Liquid base cytology - Auto PAP screening Visual inspection with acetic acid (VIA) HPV testing Others - Cervicography

Papanicolaou test PAP test started for screening from the middle of the 20th century in the developed countries. Drawbacks of the test - 10-20% cells - air drying - false negative Decrease incidence of Ca cervix 79% mortality of Ca cervix 70% Conventional cytology Sensitivity cervical cancer precursor - 51% CIN 2 3 47-62% Specificity 60-95% False negative 49%

Liquid base cytology

Newer technique, more experience, sophisticated automated equipments require and not cost effective. 80-90% cells are transferred to the liquid media as compare to conventional cytology 10-20%. Eliminates air drying. Smear has uniform layer of cervical cells without debries. Eliminates 70-90% unsatisfactory samples.
.

Visual tests
No lab processing. Result immediate. Treatment can be provided at that time. Easy to learn and train.

Application of acetic acid 3-5% (VIA) Acetowhite area Lugols iodine application
( VILI)

Dysplastic cell will not stain

HPV DNA test

In 2003, FDA approved the use of HPV typing as an adjunct to cervical cytologic screening in women aged 30 years or older. Smear taken, lab processing and automated results. HPV DNA + cytology sensitivity > 95% specificity > 90%

Sensitivity

Specificity

Cytology HPV testing

31-78% 61-90%

91-99% 62-94%

VIA
VILI

50-96%
44-93%

44-97%
75-85%

Cervicography

Cervix is visualized after application of 5% acetic acid . After one min. two photographs taken using special designed camera Film is developed as 35 mm slide then interpreted. Sensitivity - 89 % Specificity - 92%

Colposcopy
Determine extent of lesion and useful in taking biopsies (punch biopsy). Procedure - Magnified cervix seen. - Detail of precancerous lesions of TZ - Apply NS to see the detail of cercvical capsilaries under green filter. - application of acetic acid Lugols iodine - perform biopsy if necessary.

Colposcopy
Disadvantages Expensive Require specialized training

Natural history of CIN

Patients regress persist progress to CIN 3 Progress to invasive cancer 1% 5%

CIN 1 4,504 CIN 2 2,247

57% 43%

32% 35%

11% 22%

CIN 3

767

32%

>56%

>12%

64 studies, 274 carcinomas, 15,473 CIN cases Follow up 1-12 years Ostor AG, Int J Gyne Path 1993;12:186-192

Transition time of cervical intraepithelial neoplasia

Stages Normal to mild to moderate Normal to moderate to sever Normal to carcinoma in situ

Mean years 1.62 2.2 4.51

Clinical Gynecologic Oncology, 6th ed.

Treatment options for CIN

Observation Abaltive methods Excisionla methods - Cryosurgery - LEEP - Co laser ablation - Punch biopsy - Cold cogulation - Cone biopsy - Electrocogulation diathermy

Hysterectomy

Atypical squamous cells (ACS) Incidence- 3-5% ASC-US ASC-H ASC-US associated with CIN 1 0-20% CIN 2 or 3 3-5% Triage options Repeat PAP test 4-6 months, referral for Colposcopy if abnormality Immediate Colposcopy HPV testing- detect 90% CIN 2 or CIN 3

Atypical glandular cell abnormality(2001 Bethesda system)

Atypical glandular cell(AGC) Atypical glandular cells- favor neoplatic Endocervical AIS Adenocarcinoma AGC on PAP Colposcopy and endocervical curettage- glandular abnormality- cone biopsy.

Adenocarcinoma in situ (AIS)

No specific Colposcopic features to identify AIS.

Detected on cone biopsy or on hysterectomy

Cone biopsy with negative margin is treatment of choice in young women. Hysterectomy for the women who completed family. Failure rate of excisional procedure ranges from 0-9%.

Pregnancy with CIN

No effect of pregnancy on course of CIN. Better to avoid the treatment of CIN during pregnancy. CIN III managed conservatively with Colposcopy every 3 months. LEEP is better than cone biopsy with fetal loss 5%.

Treatment of CIN l

Spontaneous regression 60-85% mostly within 2 yrs follow up. No need of treatment. Follow up every 6 months.

Treatment of CIN 2 or 3,CIS

CIN 2 and 3 should be treatment. Treated with excisional methods. - Punch biopsy- single, focal lesion - LEEP - Cone biopsy

Different treatment techniques for CIN

Ablative techniques Treated by destroying tissue of cervix which has dysplastic cells. This allows the normal cells to grow back in their place.

Ablative techniques
Indications No evidence of microinvasive or invasive cancer.

Lesion located on the ectocervix and can be seen entirely. No involvement of the endocervix with high grade dysplasia.

Cryotherapy
Destructive technique, introduced in 1960 to treat CIN. Destroys the surface epithelium of cervix by crystallisation of intracellular water. Nitrous oxide 89C, carbondioxide -65C.

Depth of Cryodestruction upto 5 mm.

Single freez- thaw cycle or double freez thaw cycyle.

Advantages Severe bleeding rare. Less PID post procedure. Local cervical infections rare. Severe pain less. Long term complications like cervical stenosis. and impact in fertility is infrequent. Post therapy healing rapid with 12 wks. Simple OPD procedure, easy to learn.

Disadvantages

Profuse watery p/v discharge -20% Slight spotting till 12-15 days SCJ not visible in many patients Failure rate depends on Grade of lesion Size of lesion - whole ectocervix - 42% - <1 cm lesion 7% Involvement of endocervical gland - with- 27%, - without- 9%

Carbon Dioxide laser ablation

Laser produces high-intensity columnar beam of light that can concentrated to a small spot. Vaporize the tissue by boiling the intracellular water causing the cell to explode. Co laser can ablate tissue or cut. Done under Colposcopic guidence.

Cold Coagulation Method of destroying abnormal cells with the use of a heated probe. Advantages Quick Non-invasive Can be done as outpatient procedure

Electrocoagulation diathermy
Oldest of local destructive techniques. Electrical current is used to coagulate tissues and through electrodes and probes. Depth of destruction upto1 cm using needle and ball electrodes. require analgesia- general, regional, local

Excisional procedures
Removes the whole area of the transformation zone- the area containing the cells that could become precancerous or develop into cervical cancer. More common and successful than ablative methods. Overal cure rate 98% Indications of excisional procedures Suspicion of invasive disease. Glandular involvement SC junction not clearly visible

Loop electrosurgical excision procedure (LEEP) LEEP was first introduced in the United Kingdom by Prendeville as large loop excision of the transformation zone (LLETZ). Modification of a small electrosurgical wire loop biopsy instrument developed by Cartier in France. Diagnostic as well as theraputic. Done under Colposcopic guidence.

 Electrocautery - Low power

- Large diameter wire

Electrosurgical high power( 35-55 watts)

- small loop wire(0.5mm)

Electrofulguration 5 mm ball electrode

- power 50 watts

Electrosurgical wire loops

Advantages of LEEP Diagnostic and theraputic. Easy to learn, teach and apply. Gives the operator opportunity to reexcise additional tissue. Intraoperative, postoperative hemorrhage (<2%). and less cervical stenosis (1%). SCJ visible in > 90% patients after procedure.

Disadvantages of LEEP
Increase preterm delivery, PPROM, low birth weight. More discharge if more fulguration. Incomplete excisional in upto 40% cases.

See and treat

LEEP is a simple procedure that can be used for both diagnosis and treatment during single office visit. Patient with abnormal PAP test Colposcopy - lesion is removed with loop electrode. Advantage - procedure done in single office visit. Disadvantage colposcopic appearance of squamous metaplasia and other minor change mimic CIN, inappropriate excision of benign lesion.

 CIN treated with small loop electrode - 275 large loop electrode - 157 ( in out patient basis, under LA) Post- treatment bleeding - <2% Post-treatment stenosis - <1% Success rate with small loop - 80% Success rate with large loop 90%
Obstet Gynecol1992 Feb;79(2):173-8

 A randomised study of LEEP versus Cryotherapy in the treatment of HSIL. Cryotherapy -159 , LEEP- 168 6-12 months follow up LEEP had cure rate of 96.4%, Cryotherapy 88.3%
J Obstet Gynaecol. 2001 Nov;21(6):617-21

Cone biopsy Indicated for HSIL on PAP test with following conditions. Endocervical glandular lesions / invasive lesions. Limit of lesions cant visualize with Colposcopy. The SCJ not seen on Colposcopy. ECC positive for CIN 2 or 3. Lack of correlation between cytology, biopsy and Colposcopy. After failure of LEEP, ablation.

 Local anesthetic( lidocaine with 1:100000 epinephrine) at site of incision, lateral sulcus 3 and 9 oclock position. Different methods - Surgical scalpel ( cold knife)- blade size10,11,15 - laser beam - Electrosurgical wire Cone should be symmetrical arround the endocervical canal, apex at canal. Sturmdorf suture for closure of bed of cone biopsy

Advantages of cone biopsy Theraputic as well as diagnostics. Allow to remove abnormal tissue by avoiding unnecessary removal of surrounding normal tissue. Effective when endocervical glands involvement and invasive lesions. Cure rate is higher.
Disadvantages of cone biopsy

Bleeding in first 24 hr or 10-21 days of procedure - 5-10% require reevaluation. - packing, suturing. Cervical stenosis - 3% Cervical incompetence Preterm labor Infections

 Expensive. 5-10% persistence or recurrence after procedure if margin is positive. Recurrence Endocevical gland involvement - 24%, Without endocervical gland involvement - 11%.

Randamized study comparing conization verses LEEP( CIN ll, CIN lll) Mean height of cone specimen Cone biopsy -18.9 mm LEEP - 12.8 mm Clear margin Cone biopsy -100% LEEP- 80% Visible SCJ Cone biopsy -39% LEEP 71% Success rate Cone biopsy 90% LEEP- 79%
Gynecologic Oncology (1999)Vol: 75, Issue: 3, Pages: 356-360

Hysterectomy
Hysterectomy is currently too radical for treatment of CIN. Indications Repeated recurrence after conservative methods. Microinvasion. CIN 3 at limits of Conization specimen. Poor compliance with follow up. Associated with other gynecological problems (fibroid, prolapse, emdometriosis)

Postoperative follow up
CIN l with positive margins should have cytologic testing at 6 &12 mon.or high-risk HPV testing at 12 mon. Positive margins for CIN 2, 3 or a positive endocervical sampling, Follow-up with endocervical sampling.
ACOG , Practice Bulletin

High-risk HPV typing may be an alternative to cytologic testing after therapy for CIN 2, 3 for women aged 30 years or older, 6 months following therapy After treatment for CIN 2, 3, cytologic testing 3-4 times at 6-month intervals is recommended.
ACOG , Practice Bulletin

Prevention of CIN
HPV vaccine. Avoid sex in early age. Avoid multiple sexual parters. Use of condom. Avoid smoking. HPV vaccine In Nepal NNCTR providing the HPV Vaccine (Gardasil) for school girls 11-13 yrs age group from 2008. Vaccine has to be given before the sexual activity.

HPV Vaccine Decrease the incidence of cervical cancer and its precursor lesions. Bivalent for HPV 16 and 18( Cervarix) Quadrivalent for HPV 16,18,6,11( Gardasil) prevents 70% cervical cancer 90% genital warts 0.5 ml Gardasil schedule 0,2,6 0.5 ml Cervarix 0,1,6 The HPV vaccine for women from age 9 - 26 to prevent cervical cancer and genital warts. FDA in 2006

Conclusions
Effective cervical screening, diagnosis and treatment of premalignant lesion of cervix reduces the incidence of cervical cancer and mortality from cervical cancer.