Cervical Cancer

Wilson and Jungner

Created a criteria that any screening programme must meet - determines the effectiveness. Helps identify precursors to cancers, as progression form precursor to invasive is well-documented and therefore leaves a big window of opportunity for treatment

WIlson and Jungner Criteria

1. Condition being screened must be an important health problem

2. Natural history of condition should be well understood

3. There should be a detectable early stage

4. Treatment at an early stage should be decided for the early stage

5. A suitable test must be devised for the early stage

6. The test must be acceptable

7. Intervals for repeat testing should be determined

8. Adequate health service provision should be made for extra clinical workload from screening

9. Risks (both psychological + physical) need to outweigh benefits

10. The costs should be balanced against benefits

Acronym for W-J

I Hate Dylan, Thanks To All of his Rambling, People Ran Cowardly

(Importance, history, detectable, treatment, testing, acceptable, repeat, provisions, risk, costs)

Age-Specific Incidence

• Peak in ppl 30-34

• Only 9% of new CC cases in the UK are 75+

Histological Types of Cervical Cancer

• Squamous Cell Carcinoma: 80-90%

• Adenocarcinoma: 10-20%

• Adenosquamous carcinoma: Rare, 3-10%

• Neuroendocrine Carcinomas: Very rare, less than 5%

• ADSC + NEC = aggressive, quick progression

Pathogenesis

• 99% of CC linked to high risk HPV

• Over 200 types, 12 oncogenic

• HPV 16 & 18 cause around 70% of CC + pre-cancerous legions

• High risk HPVs also involved w squamous cell carcinomas in vagina, vulva, penis, anus, tonsils & oropharynx

• Low-risk e.g. 6 and 11 cause genital warts but not cancer

• Belongs to DNA viruses according to genetic sequence

What is HPV?

• Baltimore Class I virus

• Double stranded circular DNA

• Only infect immature basal cells of squamous epithelium (through micro-tears in epithelialium or metaplastic squamous cells)

HPV Clearance

• Most infections are asymptomatic, cleared by immune system (70% within 1 year, 90% within 2 years)

• Persistent HPV (especially high-risk or ppl w weak immune system) increase risk of malignancy

Viral Proteins E6 and E7

• Interfere w tumour suppressor proteins that regulate cell growth and survival

• HPV infects immature squamous cells in basement membrane and then replicate in as they mature and reach the top

• Mature cells usually rest in G1 phase, but progress through cell cycle if infected with HPV

• HPV uses host DNA synthesis machinery to replicate its own genome

• E7 binds to active form of retinoblastoma, promote degradation to protostome pathway

• Inhibits p21 and p27 - important cyclin dependant kinase inhibitors

• Cell cycle progresses, DNA damage repair is damaged

• E6 binds to TSP p53 - promotes degradation + up regulates telomerase, leads to cellular immortalisation

• Overall increased cells + more mutations

• Low-risk viruses bind w lower affinity to retinoblastoma, E6 fail to bind p53 - why they are not oncogenic

• Low-risk dysregulates growth and survival by interfering with notch signalling pathway

• Viral DNA integrates to host genome > inc. expression of E6 and E7, interferes with oncogenes e.g. MIC

HPV Vaccines

• Two are licensed

  • Cervarix protects against high-risk e.g. 16, 18

  • Gardasil 9: protects against low risk

• Most ppl under 25 require one dose, but immunocompromised require 3

• Gardasil offered to all children 11-12, catch-up available under NHS until 25

• Doesn’t protect all oncogenic HPV

• No waning immunity

Cervical Screening

• Pap smears

• Where they are not common + vaccines are not common = CC stays a major threat, therefore early detection important

• Pre-cancerous changes are known as Cervical Intraepithelial Changes (CIN) - gives us time as it progresses

NHS Cervical Screening Programme (1988)

• Early detection + treatment = prevention of 70% of CC deaths, if everyone attended regularly could increase to 83%

  • many ppl avoid due to things such as trauma, cultural + religious concerns, accessibilities, learning differences, gender dysphoria and other practical barriers

• For indviduals with a cervix:

  • ages 25 to 64 years every 5 years

  • people w HPV/cell changes are invited more often

• UK National Screening committee recommended that NHS CSP adopt high-risk HPV testing as the primary screening method (2016)

HPV Primary Screening (2016)

• Reversed traditional process: HPV testing first, and then cytology examined only if HPV is positive for high risk (reduced CC incidence compared to morphology-first screening)

• Streamlining workload by only looking at what needs to be investigated

• Ppl w low-risk have low chance of developing CC - back into routine recalls (5 years)

• Systems employ PCR or nucleic acid hybridisation to identify high-risk HPV and then examine by microscope to check if has caused CIN

The Cervix

• Ectocervix

  • Part of cervix visible during examination

  • Covered by immature squamous epithelia, extends to vaginal walls

  • Center: small opening called external os - gateway into endocervical canal

• Endocervical canal

  • Columnar epithelium, secretes mucus

  • Meeting point between two types called squamocolumnar junction

• Squamocolumnar junction

  • Not fixed, changes in response to age and hormonal levels

  • Moves upwards into endocervical canal over time

• Squamous metaplasia - where glandular epithelium is replaced by squamous epithelium

• Happens at the transformation zone

• Trans zone susceptible to infection

• Important to visualise OS so that cells are taken from trans zone

Sample Collection - Cervical Smear

• Speculum inserted and widened so cervix can be seen and sample can be taken

• First visually inspected for irregularities

• Instruments include spatula (wood, plastic), endocervical brush that can be swivelled, cervical broom (nylon - best!)

• Cervical broom conforms to natural shape of cervix, flexes - top of brush can be detached and placed in preservative, dispensed in solution

• Reduces blood from interfering with specimen, reduces amount of mucous

Liquid-based cytology

• Prevents mucous and cells overlapping - provides cleaner background, more accurate examination

• Cells in sample pot are agitated off broom by vortex, removed and then analysed

• Uniform distribution on slides allows for automated screening - combines digital microscopy with AI to pre-screen, reduces workload and human-error

• UK uses SurePath and ThinPrep

  • SurePath - syringe disperses large cells from smaller fragments, then into centrifuge w density gradient reagent to trap stuff and then processes

  • Thinprep - polycarbonate filter put into vial, rotated gently to disperse large aggregates of cells, mucous and blood. Suspension homogenised, vacuum added to filter, leaves cells to appear at bottom against positively charged glass slide. Pulse of air transfers them into slide and fixed w ethanol

Acute and Chronic Cervicitis

• Lactobacilli are dominant normal flora in vagina, produce lactic acid and maintains vaginal pH below 4.5

  • As cells mature, glycogen releases and reacts to Lactobacilli - creates acidic environment for pathogenic defence

  • Disrupted by douching, SI, menstrual blood - stops Lactobacilli

• When environment becomes alkali, not as much defence - causes Cervical inflammation caused by gonococci, chlamydiae, mycoplasmas, HSV

  • Ascending infections > adverse pregnancy outcomes, makes people sterile or passes infection to partners

• Inflammation causes a reactive epithelia change, shedding squamous epithelial cells

• Inflammation can mimic CIN, generates false positives if relying on morphology alone - DNA analysis reduces false positives

Endocervical Polyps

• Common benign growths, arise from cervical canal

• Small sessile bumps to large polypoid masses that can protrude through cervical os

• Similar to skin tags, composed of loose fibrous stroma, surrounded by epithelium on outside

• In this case covered by cervical epithelium

• Cause of spotting/bleeding, suspicion of lesions

• Simple curettage or surgical excision can cure this

Dysplasia and CIN

• Dysplasia: abnormal cellular change that may precede cancer > nuclear atypic, increased nuclear to cytoplasmic ratio, nuclear enlargement, hyperchromasia, coarse chromatin, variation in nuclear shape and size

• CIN: Phase of pre invasive disease, happens before invasive squamous cell cancer

UK BSCC (British Society of Cervical Cytology) terminology

• Mild dysplasia = CIN I

• Moderate dysplasia = CIN II

• Severe dysplasia = CIN III

• Carcinoma in situ - CIN III

• CIN is histological, not cytological

• Cytology can raise suspicion but does not diagnose like biopsy

Colposcopy

Observation of cervical by binocular magnification, outpatient procedure

• Looks for visibly abnormal areas, vascular patterns

• Localise and treat CIN

• Can reassure individuals who do not require treatment

• Green filter fitted to enhance contrast, helps interpret pattern of blood vessels

• Dilute solution of acetic acid applied to surface to identify abnormal areas - can be enhanced with iodine solution swab, stains normal tissue deep brown and neoplastic epithelium pale yellow

• Punch biopsy taken for lab exam

CIN Categorisation

• 1, 2, 3 - depends on proportion of thickness of epithelium showing mature and differentiated cells

• More severe grades = greater proportion of thickness of epithelium composed of undifferentiated cells

• Most low grade CIN regress in short periods/do not progress to high-grade lesions

• High grade CIN carries higher probability of progressing to cancer

ISH and IHC

• Confirms diagnosis in dysplasia

• HPV DNA ISH visualises DNA in biopsy tissue

  • in productive HPV infection - viral genomes abundant in maturing upper epithelial cells

  • reflects viral replication as cells differentiate and migrate

• IHC uses Ki-67 to mark for cell proliferation

  • in normal squamous epithelium - staining stays at basal layer (where stem cells are)

  • dysplasia - E6 and E7 disrupt cell cycle, prevent normal growth arrest

• p16 in IHC - cyclin dependant kinase inhibitor, accumulates in response to HPV mediated inactivation of retinoblastoma pathway

• Correlate to high risk, good for cases that can’t be diagnosed e.g. CIN II

CC

• More than 50% of CC occurs in ppl who do not attend regular screening

• Cytology is screening test - diagnosis depends on biopsy and histology

• Early stage disease can be treated conservatively e.g. cone excision such as taking more cervix out

• Advanced case requires surgery e.g. hysterectomy or lymph node assessment

• Advanced disease treated by radiotherapy and chemotherapy

• At pre-cancerous stages, ablation by liquid nitrogen or cautery/biopsy can sort it out - important to treat before progression

Invasive cell carcinomas

• May manifest as either fungating masses (outwards form cervix) or infiltrating masses (deeper into surrounding tissue)

• Most common = squamous cell carcinoma

  • made of nests and tongues of malignant squamous epithelium, either keratinising or non-keratinising

  • invade underlying cervical stroma (connective tissue beneath surface epithelium)

• Basement membrane really important for separation

Adenocarcinoma

• Arises form glandular cells

• Malignant cells are large, hyperchromatic due to increased DNA, mucin depleted cytoplasm

Treatment

• If colonoscopy is confident for high grade lesion w clearly visible boundaries = see and treat approach

  • applicable for CIN but not advanced cancers

  • destroy or remove transformation zone, prevents progression to invasive cancer

• Tissue destruction by laser therapy or cold coagulation and cryotherapy

• Tissue removal by a hot wire (large loop excision, LLETZ) and cone (scalpel blade) - treatment success high

• Ppl must come back for screening - cells examine straight away

• Some cases, hysterectomy

Prognosis and Survival

• Depends on stage of cancer at diagnosis and histological type (some are more aggressive)

  • Localised (cancer confined to cervix): 5-year SR is 91%

  • Regional (spread to nearby tissues or lymph nodes): 5-year SR is 61%

  • DIstant (spread to other organs): 5 year SR is 19%