O&G JC103: Abnormal Cervical Smear: Cervical Cancer, Cancer Screening Flashcards
Why cervical cancer is a disease suitable for screening?
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
- Suitable test
- minimally invasive simple collection (i.e. cervical cytology)
- cervix accessible to early cytology collection for screening, HPV testing - Suitable screening programme (Practical + Implementable)
- HK DoH launched a territory-wide cervical screening programme in 2004 - 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 ↓
How to take a cervical smear
- Speculum of correct size
- depending on size of vagina: larger for multiparous, smaller for nulliparous, menopausal women - Adequate exposure of cervix
- Light source
- Sampling device: **Ayre’s spatula / brush / broom
- menopausal women: Os is small + Squamo-Columnar junction receded into cervical canal —> use **Endocervical brush - 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)
Proper preparation of smear / LBC
- Properly labelled slide + bottle
- Checked with patient for correct identity
- Correct preparation of smear / LBC
- ***immediately fix it on glass slide (otherwise have artifact) - 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
When NOT to take a cervical smear
- ***Blood in vagina / cervix (usually ∵ menstruation)
- ∵ blood may obscure normal cells - ***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 - Cervix cannot be seen
Causes of Unsatisfactory smear
- Artifacts
- inappropriate fixation of glass slide
- air dried / too thick / too scanty cells on smear / heavily blood stained - Inflammation / Infection
- inflammatory cells mask normal cells
—> treat infection + repeat - Menopausal
- ∵ **atrophic epithelium —> cells will look abnormal
—> apply **local estrogen + repeat - Post-treatment
- RT / Chemotherapy
What is an abnormal smear?
- Different grades of abnormal smear
- Abnormal smear =/= cancer
- Different classifications of abnormalities exist
***WHO histology classification of Tumours of Uterine cervix
- Epithelial tumours
- **Squamous cell tumours + precursors
- **Glandular tumours + precursors
- Other epithelial tumours - Mesenchymal tumours
- Mixed epithelial + mesenchymal tumours
- Melanocytic tumours
- Lymphoid + Haematopoietic tumours
- Secondary tumours
***Classification of Cervix, Vagina, Vulva neoplasms
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
The Bethesda system (TBS)
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
***Classification of Squamous cell abnormalities
- Atypical squamous cells
- of undetermined significance (ASC-US)
- cannot exclude HSIL (ASC-H) - Squamous intraepithelial lesion (SIL)
- Low-grade SIL
- High-grade SIL
- with features suspicious for invasion (if invasion suspected) - Squamous cell carcinoma (SCC)
Atypical squamous cells of undetermined significance (ASC-US)
- 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
Atypical squamous cells cannot exclude HSIL (ASC-H)
- 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)
- 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
LSIL (Low grade squamous intraepithelial lesion)
- 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
HSIL (High grade squamous intraepithelial lesion)
- 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)
***Classification of Glandular cell abnormalities
- 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) - Endocervical adenocarcinoma in-situ
- Adenocarcinoma
- Endocervical
- Endometrial
- Extrauterine
- NOS
Atypical glandular cells
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)
Adenocarcinoma in-situ (AIS)
- 48-69% confirmed AIS
- 38% Adenocarcinoma
Management:
1. Colposcopy + Biopsy
2. Endocervical sampling
3. Endometrial sampling
4. Cone biopsy (if no lesion)
Recent advances in Cytopathology
- Gynaecological cytopathology reporting system
- TBS - 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) - Modern cytology laboratory management
- Quality control + Accreditation
Clinical application of HPV test
- ***Primary screening
- ***Triage of ASC-US
- Test of cure —> Determine risk for persistent / recurrent disease
Ultimate purpose: ***Detection of HSIL + Carcinoma
Considerations of Effective screening
- 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) - Target population?
- 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) - 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 - Follow-up of abnormally screened people
- 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
Current status of cervical screening in HK
- 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%
How to manage abnormal screening results?
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
Colposcopy
- 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
- 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
- High grade lesions:
—> ***Cone biopsy
***Treatment of Low grade CIN + High grade CIN
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
-
**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) - 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
LLETZ: large loop excision of transformation zone of cervix (子宮頸電圈切除)
- 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
***Treatment of Early invasive cervical cancer
- Radical hysterectomy with Bilateral pelvic lymphadenectomy
- RT
- 85% 5-year survival rate
Primary prevention of cervical cancer
- Healthy lifestyle
- Safer sex
- Vaccine
Screening: ***Secondary prevention
HPV vaccines
- 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
Summary
- 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
