Liquid base cytology

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1 Early Detection of Cervical Carcinoma

2 Contents Introduction Screening of Cervical cancer HPV and cervical cancer Management of abnormal cervical smear Colposcopy

3 Introduction

4 Cervical carcinoma 2 nd most common Cervical cancer is the female malignancy world-wide In Hong Kong, it is the 4 th commonest female cancer, it accounts for: 6% of all newly diagnosed cancer 4% of all cancer death :

is the 4 th commonest female cancer, it accounts for:

5 Risk factors for cervical cancer Age after 55 Sexuality: Age at first intercourse: < 20 years old Numbers of sexual partners Human papillomaviruses: type 16, 18, 31, 33, 35, 51 etc. Smoking Occupation Parity: higher parity Socioeconomic class: lower social class

partners Human papillomaviruses: type 16, 18, 31, 33, 35, 51 etc.

6 Screening of cervical cancer ( ) / cervical smear: Pap s/cervical smear Classification of smear Different terminologies How to obtain a good cervical smear Common problems of false negative result frequency of cervical screening

terminologies How to obtain a good cervical smear Common

8 Vaginal smear 1928, Dr Papanicolaou detected cervical cancer cells in a vaginal smear 1928 Papanicolaou 1943, Papanicolaou and Traut published Diagnosis of uterine 1943 Papanicolaou Traut smear cancer by the vaginal

1943, Papanicolaou and Traut published Diagnosis of

9 - Screening for cervical cancer and it s precancerous lesion cervical smear ( ) In 1940s, Dr. George Papanicolaou introduced his test for cervical cancer ( ) In 1960s, Pap smear has been widely used to detect cancerous and precancerous cervical lesion Death due to cervical cancer reduces by 70%.

George Papanicolaou introduced his test for cervical cancer ( ) In 1960s,

10 ( ) (1954) Cervical smear Papanicolaou classification I abnormal cell II III malignancy IV V Class I: no atypical or Class II: atypical cells detected but no features of malignancy Class III: suspicious of Class IV: malignancy is highly suspected Class V: malignant cells detected

cells detected but no features of malignancy Class III: suspicious of

11 Bethesda (1988 National Cancer Institute - NCI) Within normal limit : Abnormal epithelial cells Squamous cells Atypical squamous cells of undetermined significant (ASCUS) Low grade squamous intraepithelial lesions (LGSIL: HPV, CIN I) High grade squamous intraepithelial lesions (HGSIL: CIN II, III)

undetermined significant (ASCUS) Low grade squamous intraepithelial

12 Bethesda (1988 National Cancer Institute - NCI) Abnormal epithelial cells: Glandular cells Endometrial cells Atypical glandular cells of undetermined significant Endocervical adenocarcinoma Endometrial adenocarcinoma Extrauterine adenocarcinioma

glandular cells of undetermined significant Endocervical

13 Other terminology 1969, Richart and Barron: ( ) Cervical intraepithelial I, II, III neoplasia (CIN): I, II, III Classical and KOPAC: Mild dysplasia Moderate dysplasia Severe dysplasia Carcinoma in situ

14 Different terminologies Classical & KOPAC CIN I Mild dysplasia Moderate dysplasia CIN II Severe dysplasia CIN III Carcinoma in situ Bethesda LGSIL HGSIL (Pap s) III IV

15 ( ) Cervical intraepithelial neoplasia (CIN) and cervical cancer CIN I Duration from CIN I to 10 ( ) cancer: 10 years (?) CIN Risk from CIN to cancer: 15% CIN I : 15% CIN II : 30% CIN III : 45% Overall risk: 15% CIN I : 15% CIN II : 30% CIN III : 45% Cervical cancer can be preventable if high grade CIN is treated

) CIN Risk from CIN to cancer: 15% CIN I : 15% CIN II : 30% CIN III : 45%

16 Taking Cervical Smear The cervix must be in full view Ayres spatula: commonly Ayres used the small pointed end is placed at the external os, as high as possible into the endocervical canal / 360 rotated 360 o about the os with firm but gentle pressure entire transformation zone must be included

as high as possible into the endocervical canal / 360 rotated 360 o about

18 Take a cervical smear

19 Taking Cervical Smear The secretion on the spatula is spread evenly on the glass slide The slide should be fixed immediately and without drying by immersing in absolute alcohol or with the spray Avoid to take a smear during bleeding or menstruation

immediately and without drying by immersing in absolute

20 Squamous columnar junction

21 Satisfactory cervical smear Adequate amount of cells Indicator cells must present Columnar cells Endocervical origin Immature metaplastic cells From transformation zone

22 Problems of cervical screening 36 High false negative smears results about 16-36% Two reasons: Inadequate cell sample abnormal cells are missed or misinterpreted

23 The major causes of false negative Sampling error: 90% Detection (screening error : 10%

24 Sampling error Upto 80% of the cervical cells collected are thrown away with the collection device Upto 40% of all conventional cervical, smears are compromised by blood, muscus, and inflammation

25 Liquid base cytology The Thinprep system is one of the liquid-based cytology preparation system approved by the U.S. Food and Drug Administration Department 1996 (FDA) in 1996 as a replacement test for the conventional Pap smear for cervical cancer screening AutoCyte, The other system, the AutoCyte, has applied for FDA clearance

27 Why does ThinPrep make a difference? The ThinPrep system,, limitations of the,, overcomes many of the conventionally prepared cervical smear which may be obscured by blood, mucus, debris, thick uneven smearing, air drying and fixation artifacts. The ThinPrep prepared slides, are clear, uniform and reproducible, making them easier to screen and to interpret the cellular changes

29 Why does ThinPrep make a difference? Almost the whole sample is preserved, allow HPV typing and computer- assisted automated analysis (PAPNET system) Clinical studies has demonstrated significant reduction of unsatisfactory smears from 3.5% to 0.2% and reduction of less than optimal slides by 54%, Increased detection of Low Grade SIL or higher abnormalities, 3.5% 0.2%, 54%

30 Conventional cervical smear VS ThinPrep Pap test : Significant decrease the number of: unsatisfactory specimen specimens diagnosed as ASCUS and AGUS Significant increase : in the detection of: LGSIL ThinPrep Pap test: HGSIL

31 Duration of screening Screening frequency (in years) % Reduction in Cumulative risk 93.3% 93.3% 91.4% 83.9% 64.2% No of tests in age range

32 Human papilloma virus (HPV) & cervical cancer

33 Human papilloma virus (HPV) & cervical cancer 90 More than 90 types 30 Female and male anogenital tract: Multicentre study: HPV HPV DNA presents in 93% 94% CIN 30 different types 93% of cancer specimen 94% of CIN lesion

34 Human papilloma virus (HPV) & cervical cancer 3 groups: 3 Oncogenic potential: 16, 18, 45, 56 High grade lesion, invasive cancer of cervix vulva, penis, anus 6 11 No oncogenic potential: 6, 11 Begnin condition, condyloma acumunata, occasionally low grade lesion Intermediate oncogenic potential 31, 33, 35, 51, 52 High grade lesion, rarely invasive anogenital cancer

35 Human papilloma virus (HPV) & cervical cancer Koutsky et al (1992): HPV DNA 28% HGCIN HPV DNA 3% HGCIN Cuzicket (Lancet, 1995) 44%CIN II-III HPV Koutsky et al (1992): 2 year follow-up for women with negative smear but positive HPV 28% developed to HGCIN negative smear and HPV only 3% developed to HGCIN Cuzicket (Lancet, 1995): 44% women with CIN II-III were only picked up by HPV testing while those smears were negative HPV 95% Cervical smear and HPV typing can detect 95% HGCIN

36 HPV Clinical applications for HPV DNA testing HPV HPV HPV DNA testing: To detect women with high risk HPV for long term follow-up To detect precancerous lesion earlier To prevent cervical cancer Problems encountered: HPV HPV % 59 5% Sexual and psychological disturbance Infection rate: positive rate for HPV years: 20% 59 years: 5%

37 Management of abnormal cervical smear

38 Management of abnormal cervical smear HKCOG guideline Management of smears of ASCUS and LGSIL ASCUS-LSIL Triage Study (ALTS)

40 HKCOG guideline Cervical smear Normal 0.1% CIN II-III ( 1996 ) Suggestion ( ) Inflammation 3-6 changes

41 HKCOG guideline ASCUS LGSIL HGSIL ASCUS 14% CIN II-III 0.7% 0.2% 13.4% CIN II-III 0.1% 69.5% CIN II-III 2.3% 3.5% 3-6

42 HKCOG guideline 53.8% AGUS 17% HG 5% AIS( ) 2% ( ) 7% 13% 38%

43 Management of smear with ASCUS Information from USA: 5% ASCUS LGSIL 2% 3 ASCUS LGSIL About 5% cervical smears are reported as ASCUS, 2% as LGSIL ASCUS or LGSIL is affecting more than 3 million women every year : If all were referred for colposcopy: Not cost effective Unnecessary anxiety caused

44 ASCUS-LSIL Triage Study (ALTS) Research centres all in USA Study period : from Jan to Jan Number of patients 3488 women with cervical smears of ASCUS Patients were divided into 3 groups 1. HPV DNA typing (Hybrid Capture 2): high risk HPV (16,31,33,39,45,51,52,56,58,59,68) colposcopy 2. Cervical smear: HGSIL colposcopy 3. Colposcopy directly

45 ASCUS-LSIL Triage Study (ALTS) HPV Cervical smear Colposcopy High risk HGSIL (53.1%) (67.1%) (100%) colposcopy CIN III CIN III CIN III 8.7% 9.3% 8.3%

46 ASCUS-LSIL Triage Study (ALTS) Conclusion HPV DNA typing could be as effective as colposcopy to detect HGSIL in women with smears of ASCUS HPV DNA ASCUS Half the numbers of colposcopy required

47 Colposcope

48 Colposcope Hans Hinselmann It was invented by 1925 Hans Hinselmann in It was not popular used in English speaking countries until 1960s

50 Colposcopy Examination Outpatient procedure : Colposcope : low power binocular microscope 6 40 stereoscopic view of the cervix at magnification of x 6 to x 40

51 Colposcopy Examination Indications: abnormal cervical smear: squamous intraepithelial lesion (LGSIL or HGSIL) repeated smears showing atypical squamous cells of unknown significant (ASCUS) suspicious of cervical cancer clinically persistent postcoital bleeding

53 Colposcopy Examination bivalve speculum 3-5% acetic acid: 3-5% ( ) (Schiller s iodine test) Lithotomy position The cervix is exposed with a coagulates the proteins of the nucleus and cytoplasm aceto-white epithelial (dysplastic cells are most affected) Lugol s iodine (Schiller s iodine test): identify the normal epithelium, which is stained into deep brownish, with large amount of glycogen in the cytoplasm

54 Satisfactory Colposcopy Examination The entire transformation zone should be visualised The whole lesion should be seen

56 Colposcopy Examination Terminology: aceto-white lesion punctation mosaic atypical vascular pattern

59 Colposcopy Examination ( ) ( ) (CIN/VAIN/VIN) Purpose: identify abnormal squamous epithelium identify cervical (vaginal/vulval) premalignant disease cervical (vaginal/vulval) intraepithelial neoplasm (CIN/VAIN/VIN) rule out invasive cancer Colposcopic guided Cervical biopsy

60 Cervical biopsy Histologic diagnosis: abnormal amount of increase in mitotic chromatin in the nucleus increase of nuclear size, decrease in cytoplasm activity increase in number of nuclei loss of cellular glycogen

61 Histology Diagnosis of CIN lesion I III CIN I CIN II CIN III Grade:I to III CIN I: involves the lower third of epithelium CIN II: involves the middle third CIN III: involves the outer third the basal layer is not involved

62 Conclusion The early detection and diagnosis of cervical cancer is depending on: Identifying the high risk group Providing regular and effective cervical screening Recognising the early symptoms of cervical cancer Combining the use of colposcopy and cervical biopsy Cervical smear can prevent cervical cancer effectively but can t replace colposcopy and cervical biopsy

63 Conclusion Liquid base cytology technique increases the detection rate and reduces the rate of false negative Patients with abnormal smear or suspicious clinically should be referred for colposcopy HPV DNA testing can help to triage patients with borderline (ASCUS) smears effectively to increase the detection rate of HGCIN but reduce the numbers of unnecessary colposcopy HPV DNA (ASCUS)

子宫颈癌（Carcimoma of Cervix uteri）

子宫颈癌（Carcimoma of Cervix uteri） Carcimoma of Cervix uteri Carcimoma of Cervix uteri 13.15 13.15 1/3 40 Etiology Etiology 18 18 20 Centain infection with virus 1 transformation zone 2. Development of cervical carcer I mild (grade I) 1/3