O&G JC103: Abnormal Cervical Smear: Cervical Cancer, Cancer Screening

Question 1

Why cervical cancer is a disease suitable for screening?

Answer 1

Screening:
- Detect disease among healthy population (i.e. people without symptoms of disease)
- work best in cancer with high prevalence e.g. cervical cancer

Epidemiology of cervical cancer in HK:
- 7th incidence
- 8th mortality
- median age 54

***Wilson and Jugner criteria for disease screening:
1. Suitable disease
- early treatment is effective
- long progression from pre-cancer stage to invasive stage

2. Suitable test
   - minimally invasive simple collection (i.e. cervical cytology)
   - cervix accessible to early cytology collection for screening, HPV testing
3. Suitable screening programme (Practical + Implementable)
   - HK DoH launched a territory-wide cervical screening programme in 2004
4. Cost
   - cost-effective screening test (cervical cytology affordable)

Cervical cytology:
- Effective in reduction in cervical cancer mortality since introduction of Pap smear screening
- Proven value for mass screening
- Screening index ↑ —> Incidence ↓

Question 2

How to take a cervical smear

Answer 2

1. Speculum of correct size
   - depending on size of vagina: larger for multiparous, smaller for nulliparous, menopausal women
2. Adequate exposure of cervix
3. Light source
4. Sampling device: **Ayre’s spatula / brush / broom
   - menopausal women: Os is small + Squamo-Columnar junction receded into cervical canal —> use **Endocervical brush
5. Transformation zone (Squamo-Columnar junction: usually start of cervical neoplasia)
   - rotate clockwise 5 times —> transfer brush to vial (Liquid-based cytology) —> rinse brush / spatula + swirl broom vigorously —> cells into liquid —> send for histology
   - ***Liquid-based cytology (LBC):
   —> clearer background for morphological assessment of cells
   —> ↓ unsatisfactory smear
   —> ↑ LSIL +/- HSIL detection rate
   —> ↓ ASCUS:SIL ratio (i.e. more definitive diagnosis can be achieved)

Question 3

Proper preparation of smear / LBC

Answer 3

1. Properly labelled slide + bottle
2. Checked with patient for correct identity
3. Correct preparation of smear / LBC
   - ***immediately fix it on glass slide (otherwise have artifact)
4. Properly fill in request form with matched identity

Information on request form:
1. ***Clinical data
- helps cytopathologists to make correct diagnosis
2. Age
3. LMP, duration of menopause
4. Parity
5. Contraceptive history
6. Drug / Medical history

Question 4

When NOT to take a cervical smear

Answer 4

1. ***Blood in vagina / cervix (usually ∵ menstruation)
   - ∵ blood may obscure normal cells
2. ***Obvious / gross growth on cortex —> Biopsy more appropriate
   - ∵ cancer: necrotic cells covering cancer —> cytology only pick up necrotic cells rather than cancer cells —> miss Dx of cancer
3. Cervix cannot be seen

Question 5

Causes of Unsatisfactory smear

Answer 5

1. Artifacts
   - inappropriate fixation of glass slide
   - air dried / too thick / too scanty cells on smear / heavily blood stained
2. Inflammation / Infection
   - inflammatory cells mask normal cells
   —> treat infection + repeat
3. Menopausal
   - ∵ **atrophic epithelium —> cells will look abnormal
   —> apply **local estrogen + repeat
4. Post-treatment
   - RT / Chemotherapy

Question 6

What is an abnormal smear?

Answer 6

• Different grades of abnormal smear
• Abnormal smear =/= cancer
• Different classifications of abnormalities exist

Question 7

***WHO histology classification of Tumours of Uterine cervix

Answer 7

1. Epithelial tumours
   - **Squamous cell tumours + precursors
   - **Glandular tumours + precursors
   - Other epithelial tumours
2. Mesenchymal tumours
3. Mixed epithelial + mesenchymal tumours
4. Melanocytic tumours
5. Lymphoid + Haematopoietic tumours
6. Secondary tumours

Question 8

***Classification of Cervix, Vagina, Vulva neoplasms

Answer 8

Bethesda system (based on Cytology), WHO classification (based on Biopsy):
Binary system of diagnosis:
1. Low grade SIL
2. High grade SIL

Progression of HPV infection from Mild dysplasia —> In-situ —> Microinvasive carcinoma:
- Old classification: Condyloma —> CIN1 (mild dysplasia) —> CIN2 (moderate dysplasia) —> CIN3 (severe dysplasia - in-situ carcinoma)

• New classification:
  —> Condyloma, CIN1 —> now known as **LSIL
  —> CIN2, CIN3 —> now known as **HSIL

5th edition WHO classification of female genital tumours:
***HPV status need to be specified in Epithelial tumours of uterine cervix
—> to facilitate more accurate evaluation of impact of HPV testing + vaccination in cervical cancer prevention
—> HPV-associated / HPV-independent

HPV status ascertained by:
1. **HPV molecular testing
or
2. **p16 immunohistochemistry

Example:
Tumours of Uterine cervix: Squamous cell tumours + precursors
1. Squamous Intraepithelial lesions (SIL)
2. SCC, HPV-associated
3. SCC, HPV-independent
4. SCC, NOS (not otherwise specified) (if condition not allowed)

Tumours of Uterine cervix: Glandular tumours + precursors
1. Adenocarcinoma in-situ, HPV-associated
2. Adenocarcinoma in-situ, HPV-independent
3. Adenocarcinoma, HPV-associated
4. Adenocarcinoma, HPV-independent, Gastric type
5. Adenocarcinoma, HPV-independent, Clear cell type
6. Adenocarcinoma, HPV-independent, Mesonephric type
7. Adenocarcinoma, others

Question 9

The Bethesda system (TBS)

Answer 9

Most widely adopted cervical cytology reporting system

Standardised terminology + reporting of cervical cytology
- Processing methods (i.e. Specimen types)
- Ancillary techniques
- Automation

Evolution in concept in cervical carcinogenesis:
- Identification of **HPV as a **carcinogen of cervical cancer
- Merging of **Dysplasia + **Carcinoma-in-situ into ***SIL (Squamous intraepithelial lesion)
—> based on behaviour, molecular virologic findings, morphologic features

Question 10

***Classification of Squamous cell abnormalities

Answer 10

1. Atypical squamous cells
   - of undetermined significance (ASC-US)
   - cannot exclude HSIL (ASC-H)
2. Squamous intraepithelial lesion (SIL)
   - Low-grade SIL
   - High-grade SIL
   - with features suspicious for invasion (if invasion suspected)
3. Squamous cell carcinoma (SCC)

Question 11

Atypical squamous cells of undetermined significance (ASC-US)

Answer 11

• Most common cytological abnormality detected in screening population (60-80%)
• 3-4% of overall screening cytology
• majority turn out to be normal / LSIL
• 5-17% HSIL
• 0.1-0.2% Invasive (i.e. Carcinoma (self notes))
• ***Higher risk of subsequent confirmation of LSIL / HSIL compared with general women population
• ***ASCUS:SIL ratio used as bench marking for performance of cytology laboratory

Management of ASC-US smear (with / without HPV triage / co-testing)
1. **Repeat cytology (at 6 + 12 months)
or
2. Together with **high-risk HPV test (as triage / part of co-testing)
—> Either one positive / persisting abnormality —> ***Colposcopy
—> Both normal / negative —> Repeat cytology / with co-testing at 3 years

Question 12

Atypical squamous cells cannot exclude HSIL (ASC-H)

Answer 12

• More worrying
• Display abnormalities that fall short of diagnosis of HSIL
• ***24-94% HSIL

ASCUS/LSIL triage study:
- ASC-H associated with ***higher detection rate of oncogenic HPV + subsequent identification of underlying CIN2 / above (HSIL) (compared to ASC-US)

Management:
1. **Colposcopy + **Biopsy
—> Endocervical sampling if unsatisfactory colposcopy (i.e. cannot see Squamo-columnar junction)

2. If no lesion identified —> review cytology by pathologists —> if no change in diagnosis
   —> repeat cytology ***6 monthly
   —> repeat colposcopy if persistent abnormal cytology
   —> refer back to routine screening (every 3 years) if cytology normal twice

Question 13

LSIL (Low grade squamous intraepithelial lesion)

Answer 13

• 1.5-2.5% of smears screened
• 15-30% HSIL (CIN2-3)
• 0.1% Invasive (i.e. Carcinoma (self notes))

Management:
1. **Colposcopy + **Biopsy
2. ***Co-testing
- hrHPV positive —> Colposcopy
- hrHPV negative —> Repeat co-testing in 12 months
—> If either abnormal —> Colposcopy
—> If both normal —> Repeat co-testing / cytology in 3 years —> Routine screening

Question 14

HSIL (High grade squamous intraepithelial lesion)

Answer 14

• 70-75% confirmed HSIL (CIN2-3)
• 1-2% Invasive (i.e. Carcinoma (self notes))

Management:
1. **Colposcopy (within 6 weeks)
2. **Punch biopsy (if gross lesion seen)

Question 15

***Classification of Glandular cell abnormalities

Answer 15

1. Atypical (classified based on origin of glandular + degree of severity)
   - Endocervical cells (NOS / specify in comments)
   - Endometrial cells (NOS / specify in comments)
   - **Glandular cells (NOS / specify in comments)
   - Endocervical cells (favour neoplastic)
   - **Glandular cells (favour neoplastic)
2. Endocervical adenocarcinoma in-situ
3. Adenocarcinoma
   - Endocervical
   - Endometrial
   - Extrauterine
   - NOS

Question 16

Atypical glandular cells

Answer 16

AGC-NOS:
- 9-41% HSIL, AIS, CA

AGC-FN:
- 27-96% HSIL, AIS, CA

Management
1. **Colposcopy + **Biopsy
2. **Endometrial biopsy (Endometrial sampling first for AGC NOS, endometrial cells)
3. **Endocervical sampling
4. Pelvic USG (to exclude adnexal / extrauterine lesions)

AGC-FN:
- if no significant pathology explaining source of abnormal cells —> diagnostic cold knife cone (Cone biopsy) is recommended (ablative procedure unacceptable)

Question 17

Adenocarcinoma in-situ (AIS)

Answer 17

• 48-69% confirmed AIS
• 38% Adenocarcinoma

Management:
1. Colposcopy + Biopsy
2. Endocervical sampling
3. Endometrial sampling
4. Cone biopsy (if no lesion)

Question 18

Recent advances in Cytopathology

Answer 18

1. Gynaecological cytopathology reporting system
   - TBS
2. Modern laboratory techniques (Ancillary techniques)
   - Automation in cytology preparation
   - Liquid-based cytology
   - Computer-assisted automated screening —> Computer help to find abnormal cells within a smear —> Reduce human error
   - Application of molecular tests + IHC (esp. ***HPV tests)
3. Modern cytology laboratory management
   - Quality control + Accreditation

Question 19

Clinical application of HPV test

Answer 19

1. ***Primary screening
2. ***Triage of ASC-US
3. Test of cure —> Determine risk for persistent / recurrent disease

Ultimate purpose: ***Detection of HSIL + Carcinoma

Question 20

Considerations of Effective screening

Answer 20

1. When to start?
   - balance between minor abnormality if started early vs chance of missing cancer if started later
   - HKCOG/HKSAR recommendations:
   —> start at **25 yo / **commencement of sexual life (whichever is **later) (∵ minor abnormality is common before 25 + cervical cancer is rare)
   —> stop at **65 yo
   —> women >65 who ***never had cervical smear should be screened
   —> taking smear during pregnancy may induce bleeding + anxiety to woman (not the best time to perform cervical screening)
2. Target population?
3. How frequent?
   - balance between cost of frequent interval vs chance of missing cancer if too infrequent
   - HKCOG/HKSAR recommendations:
   —> **3-yearly intervals (after **2 consecutive normal annual smears)
   —> annual screening advised for high risk people developing cervical cancer (e.g. **immunosuppressed, **HIV women)
4. How to organise?
   - organised screening more effective than opportunistic screening (i.e. when women turns up at clinic for unrelated issues)
   - need a **central registry —> know who has been screened / should be screened + when to better organise the programme
   - can send **reminders if not turn up when due for screening / further management
   - to trace defaulters esp. those with ***abnormal results —> treat abnormal early lesions to prevent further progression + treat early cancer asap
5. Follow-up of abnormally screened people
6. How to reach people
   - public education
   - health workers education
   - mass media
   - school education
   —> conscious of need for screening + where can get screening
   —> health professionals other than doctor should promote to women of appropriate age
   —> DoH: Women’s health centre, Well women clinics, Family planning association
   —> Mobile units to reach out

Question 21

Current status of cervical screening in HK

Answer 21

• Launched on March 8, 2004
• Central registry (CSIS): need consent by women to join (unlike UK: eligible women will be enrolled without need of consent —> can get population data easily)
• Publicity
• Public education + training + education of medical personnel, smear takers
• Cytology pathology laboratory accreditation according to QA criteria
• Colposcopy accreditation according to QA criteria
• Audit on screening performance (based on CSIS)

Current status:
- CSIS: only ~20% of female (25-64) enrolled —> need to encourage more women to enroll
- <50% eligible women are regularly screened
- only 61% eligible women are ever screened (far from satisfactory, ***>=80% should be achieved)
- those who need the procedures most are least likely to get it
—> even if ↓ margin of unscreened women
—> not ↓ population risk of disease by same amount

CSIS 2018:
- Unsatisfactory specimen rate remains low
- Satisfactory cervical cytology tests: 95% were negative for Intraepithelial lesion / malignancy (5.7% abnormalities detected)
- AS-CUS, LSIL most common (5.2% of all satisfactory results)
- HSIL: 0.1%

Question 22

How to manage abnormal screening results?

Answer 22

Depends on grade of abnormality (Atypical cells to Carcinoma)
- Find out whether have pre-invasive lesions + deal with appropriately
- Offer appropriate treatment if cancer

Options:
1. Mild: Repeat cytology / HPV test
2. Suspicious: Refer colposcopy + biopsy for histological diagnosis
3. Obvious lesions: Biopsy (e.g. punch biopsy)

SpC Revision:
1. Benign looking endometrial cells
- investigate if postmenopausal or >=45 and symptomatic
- treat as normal if <45
2. Unsatisfactory
- repeat cyctology in 2-4 months
3. Absent transformation zone
- manage as normal

Question 23

Colposcopy

Answer 23

• Binocular optical instrument
• Magnify cervix 8-25x through speculum
• 3% Acetic acid: to pick up abnormal area (Aceto-white lesions, observe abnormal vascular pattern —> Mosaic / Punctations appearance)
• ***Lugol’s iodine (Schiller’s test): Adjunctive test to pick up abnormal area (Normal area stained dark brown while abnormal area not pick up stain)

Role of colposcopist:
1. Identify worst area —> biopsy
- dense acetowhite, abnormal vascular patterns (mosaic / punctation area)
- Lugol’s iodine negative area
- can be >=1 area —> multiple bites of biopsy

2. Satisfactory examination
   - need to identify whole abnormal lesion + whole squamo-columnar junction

Unsatisfactory examination:
1. Low grade lesions:
- cannot see SCJ —> review cytology by pathologist + **Endocervical sampling —> if persists —> **Cone biopsy
- **local estrogen cream for menopausal women —> repeat Colposcopy
- if whole lesion cannot be seen —> **Cone biopsy to rule out abnormalities high up in endocervical canal

2. High grade lesions:
   —> ***Cone biopsy

Question 24

***Treatment of Low grade CIN + High grade CIN

Answer 24

Low grade CIN:
- if already histologically proven to be low grade lesion
- Majority of Low-grade CIN **regressed spontaneously (usually over 2 years)
- Follow up every **6 months by Cytology until normal —> Routine screening
- Consider treatment if persisted 2 years
- If patient not reliable for follow-up —> Treatment can be offered at diagnosis

High grade CIN:
1. Ablative therapy (no histology ∵ lesion destroyed)
- Cryotherapy (-50oC)
- Cold coagulation
- Diathermy
- Laser evaporation

2. **Excision therapy (tissue intact —> can send for **histology)
   - Cone
   —> Knife (can cut deeper than loop, if want to take Endocervical sample e.g. glandular lesion (usually in Endocervical canal) (SpC Revision))
   —> Laser
   —> Loop excision (LLETZ: large loop excision of transformation zone of cervix)
3. Hysterectomy (rarely indicated unless other indications e.g. Menorrhagia)

Monitoring after treatment:
1. Cervical smear
- repeated **6 monthly until normal for **3 consecutive smear —> then annually
- 10% chance of recurrence of CIN —> important to stress to patient to follow-up

Question 25

LLETZ: large loop excision of transformation zone of cervix (子宮頸電圈切除)

Answer 25

• Done under ***LA
• Electric loop excision of cervix
• Base cauterised with ball electrode for Haemostasis
• Specimen for histology

Complications:
1. **Bleeding (intra-op / post-op) (1-8%)
2. **Infection
3. **Cervical stenosis (1%)
4. Cervical deformity
5. **Cervical incompetence
6. **Premature rupture of membrane (PROM), **Premature labour, Low birthweight

Question 26

***Treatment of Early invasive cervical cancer

Answer 26

1. Radical hysterectomy with Bilateral pelvic lymphadenectomy
2. RT

• 85% 5-year survival rate

Question 27

Primary prevention of cervical cancer

Answer 27

1. Healthy lifestyle
2. Safer sex
3. Vaccine

Screening: ***Secondary prevention

Question 28

HPV vaccines

Answer 28

• HPV found in almost all cervical cancer
• Majority of HPV infection ***cleared by itself esp. in young women <30
• ***Persistent HPV infection predisposed to cancer development
• Prevention of HPV infection —> Theoretically can prevent cervical cancer
• 14 types of HPV associated with cancer

3 types of HPV vaccines:
1. Bivalent vaccine (16, 18 —> cervical cancer)
2. Quadrivalent vaccine (16, 18 + 6, 11 —> condyloma / warts)
3. Nanovalent vaccine (6, 11, 16, 18, 31, 33, 45, 52, 58 —> additional 5 oncogenic HPV types account for >90% of cervical cancer)
—> ALL showed ~100% effectiveness in preventing HPV type specific infection + cervical lesions
—> considered safe

Normal 3 doses but:
- **2 doses within 6-12 months have similar immunogenicity in young girls (*<15) —> can be used instead of 3 doses for the 3 vaccines in young population (<15)
—> also ↑ compliance + ↓ cost

Effectiveness of vaccination also depends on:
1. Infrastructure to give vaccines
2. Acceptability by medical profession, public, government
3. Availability
4. Funding

Countries with mass vaccination + good coverage:
- ↓ in abnormal cervical cytology, HSIL
- ↓ colposcopy examination
- ↓ operative procedure required for HSIL treatment

Recommendations from HKCOG on HPV vaccines:
- Prophylactic HPV vaccines most effective with **no prior exposure to virus (i.e. never-sexually active)
- women >=15: 3 doses
- women <15: 2 doses
- **NOT given to pregnant women
- Cervical cancer screening ***still necessary after HPV vaccination

Question 29

Summary

Answer 29

• High prevalence of cervical cancer —> suitable for screening
• Cervical cytology is simple, sensitive, specific, relatively cheap
• Primary HPV testing already introduced in some countries
• Screening target population: 25-64
• Interval: **3 years after **2 consecutive normal ***annual smears / if HPV negative, repeat in 3-5 years
• Treatment of CIN simple + effective
• Treatment of Early invasive cancer has good prognosis

Primary prevention is best:
- Bivalent, Quadrivalent HPV vaccines: prevent >=70% cervical cancer
- Nanovalent HPV vaccines: prevent >90% cervical cancer
- 2020: HKSAR implementation of vaccination in girls
- Screening still recommended when reach target age (25)
- **HPV testing as primary screening: started in some countries, could be the preferred method after vaccination
- **HPV testing should not be used before 30 for primary screening (SpC Revision)

WHO pledge to eliminate cervical cancer globally by 2030:
- WHO target 90:70:90
—> 90% coverage of HPV vaccination of girls <15
—> 70% coverage of screening (70% women screened with high-performance tests by 35, 45) + 90% treatment of precancerous lesions
—> Management of 90% of invasive cancer cases