Cervical Cancer

• 6^th most common malignancy in women in Australia
• Squamous cell makes up 85-90%, adenocarcinoma 10-15%.
• Invasive cervical cancer is rare <25yo. 2 small peaks of incidence – late 30s and late 60s
• Lifetime probability in Australia is 1 in 90. 
• On average, takes at least a decade to develop from a focus of cervical squamous intraepithelial lesion
• Transformation zone is the area that almost always arises in
• HPV is found in all but 0.3% of Cervical Cancers
• Immune System clears HPV in 6 months for 50% and 2 years for 90% of women
• HPV types 16, 18 and 45 are most predominantly associated with cervical cancer, with types 16 and 18 detected in 70%–80% of cases in Australia

Risks

• Increased sexual partners
  • More than one sex partner RR>2 (RR 3 if >5 sex partners)
  • Prostitute: 4 fold increased risk 
  • Almost non-existent in virgins
• Early age of first intercourse under age 18 years (RR >2)
• Male Partner with history of multiple partners
• Tobacco use confers 1.5-3 fold increased risk (squamous cell Cervical Cancer)
• Immunosuppression
  • HIV Infection
  • Chemotherapy
  • Immunosuppressive Drugs
• Previous abnormal Pap Smear or cervical biopsy
• Lack of previous Pap Smear (50% of cancer patients)
• No Pap Smear in last 5 years (10% of cancer patients)
• History of Sexually Transmitted Disease (including HPV)
• Long term Oral Contraceptive use >5 years (2 fold increased risk)
• Lower socioeconomic class
• Uncircumcised male partner

Natural history of cervical dysplasia

• Use to be called cervical intraepithelial neoplasia (CIN), now called squamous epithelial lesion 🡪 potential for becoming invasive cervical cancer
• Progression times to cancer range from 1-30 years.  Average is 20 years. 

Presentation

• Usually on screening, usually asymptomatic. If present:
  • Vaginal bleeding, especially post-coital
  • Vaginal discharge
  • Symptoms of advanced disease, eg. Vaginal urine or flatus, weakness)

Management

• Colposcopy/Biopsy for dysplasia
• Cone biopsy – excision of cone-shaped portion of cervix
  • Includes entire transformation zone
  • Doesn’t always remove the entire lesion
• Excisional treatment with scalpel, laser or electrosurgery (eg LLETZ)
  • Large Loop Excision of the Transformation Zone – uses a thin looped wire and electrosurgical generators.
• CT, PET or MRI Pelvis may be indicated for staging
• Modified radical hysterectomy with pelvic LN sampling
• Adjuvant treatment if risk factors
  • Radiotherapy if intermediate risk factors
  • Chemoradiation if high risk factors. 

Cervical screening

• 5 yearly cervical screening
• From age 25 until 74 years
• Ever been sexually active should have test
  • Never been sexually active, doesn’t need CST screening
  • If a woman is not currently sexually active but has been in the past, still need CST
• Vaccinated still needs screening
• Liquid based medium for partial HPV genotyping

Refer immediately if

• HSIL
• Or HPV 16/18

Unsatisfactory

• Repeat in 6-12 weeks

Should have a co-test if

• Symptomatic
  • Abnormal vaginal bleeding – post coital, intermenstrual, post-menopausal
  • deep dyspareunia (in the absence of bleeding or discharge) 
  • Persistent Unexplained vaginal discharge
  • Consider referral for appropriate investigation if no cause found
• Post-menopausal women  – any episode of vaginal bleeding (including post-coital) should be investigated with a co-test and referred for gynaecological assessment.
• patients exposed to diethylstilboestrol (DES)
• patients undergoing Test of Cure (TOC) surveillance
• patients who have been treated for glandular abnormalities

• Note that abnormal vaginal bleeding can be associated with conditions such as
  • polyps
  • adenomyosis
  • leiomyomas
  • coagulopathies
  • ovulatory disorders
  • endometrial disorders
  • sexually transmitted infection
  • iatrogenic causes

• Follow up of high-grade change
  • Annual Co-test follow up for 2 consecutive negative results – then back to 5 yearly

Pregnancy

• Safe at any time
• Don’t insert the combi-brush or cyto-brush into the cervix
• Use spatula or swabs
• All people who are due for a Cervical Screening Test during pregnancy may be offered the option of self-collection of a vaginal swab for HPV testing. 
• Patients testing positive for HPV (not 16/18) on a self-collected vaginal sample should be advised to return so that a cervical sample for LBC can be collected by the healthcare provider.
• If a patient receives a positive HPV or abnormal LBC result during pregnancy, the following recommendations apply:

Previous hysterectomy

• For patients who have had a total hysterectomy for documented benign reasons (e.g. heavy menstrual bleeding, fibroids) no further tests are required if they had a normal screening history prior to their hysterectomy.
• Patients who have had a total hysterectomy with past history of HSIL should have co-testing (HPV and LBC at the same time) 12 months after treatment and annually until both tests are negative on two consecutive occasions, at which time they can discontinue screening. 
• Patients who have had a subtotal hysterectomy (i.e. cervix is not removed) should have routine 5-yearly Cervical Screening Tests, or as recommended if they have experienced a recent cervical abnormality.

Self-collection

• is an option for all patients eligible for screening (women and people with a cervix aged 25-74 years who have ever had any sexual contact), except where a co-test is indicated. 
• Cervical screening on a self-collected vaginal sample needs to be ordered and overseen by a healthcare provider. 
• The healthcare provider is not required to observe the patient collecting their sample unless this is the patient’s preference. 
• Self-collection should be routinely offered as a choice to all patients, including those from neverscreened and under-screened population groups including Aboriginal and/or Torres Strait Islander, culturally and linguistically diverse, people with disability, LGBTIQ+, lower socio-economic groups and people who live in rural and remote areas. 
• Anyone due for cervical screening during pregnancy can be offered the option of self-collection of a vaginal sample for HPV testing. 
• For asymptomatic patients, there is strong evidence that HPV tests on self-collected vaginal samples and clinician-collected cervical samples have equivalent sensitivity when using a PCR based HPV test. 
• During a consultation with a patient explain the following:
  • A self-collected sample is from the vagina (not the cervix) and can only be tested for HPV. 
  • Any cell changes cannot be seen in this sample and the cervix will not be viewed.
  • If HPV is detected in a self-collected vaginal sample, the patient will need to return for a clinician-collected sample for LBC (if HPV not 16/18 is detected) or will be referred to a specialist for further testing (if HPV 16/18) is detected).
  • Around 6% of all people who attend for cervical screening are expected to have HPV detected. 
  • That is, it is likely that the test will come back as ‘HPV not detected’.
• Not eligible if
  • if your patient requires a co-test 
  • experiencing unusual vaginal bleeding, pain or discharge
  • are undergoing Test of Cure surveillance following treatment of a HSIL result or have been treated for a glandular abnormality
  • have had a total hysterectomy with a past history of HSIL
  • have been exposed to diethylstilbestrol (DES) in utero
  • Can only be used for HPV testing
  • If 16/18 detected needs colposcopy
  • Non oncogenic needs clinical sample for LBC

Specific populations start early

• Immune deficient
• Early sexual debut < 14 – one is claimable between 20-24

Previous hysterectomy

• Total hysterectomy for a benign reason – no screening needed
• Hysterectomy for HSIL – annual co test until 2 negatives
• Subtotal – cervix present – screen as usual

Clinician-collected Cervical Screening Test – step-by-step instructions

1. A vaginal speculum examination is required to obtain a clinician-collected cervical sample and

visualise the cervix.

2. After the patient is prepared and comfortable, begin the speculum examination by examining the external genitalia for any abnormalities, then:
   1. warm the speculum, and apply a small amount of water-based lubricant
   2. hold the speculum in your hand with the handle facing down, and the blades closed
   3. gently part the labia and encourage the patient to breathe out while you slowly insert the closed speculum into the vagina using slight downward pressure, keeping the lower blade against the posterior wall of the vagina
   4. ask the patient if they are in any discomfort and encourage feedback throughout the procedure,
   5. open the blades just slightly, then tilt the speculum forward a little to allow maximum visualisation of the external orifice of the cervix uteri (external os).
3. Once the cervix is visualised, inspect for the following features:
   1. colour, size, shape
   2. position
   3. abnormal areas (lesions)
   4. surface characteristics
   5. the transformation zone (squamocolumnar junction; where the endocervical canal lining meets the squamous epithelium) which may or may not be visible
   6. discharge

4. The objective of cervical screening is to sample cells from the transformation zone of the cervix, where HPV is present and cell abnormalities that precede the development of squamous cell carcinoma are usually found.
5. When choosing a device(s), consider prior treatment and prior cytology results. Collect a sample of cells from the cervix using a spatula, brush or broom sampling device, following the manufacturer’s instructions. 

6. The choice of device depends on the location of the transformation zone, which is influenced by the patient’s age and menopausal status.
7. It is optimal for the cervical sample to contain both ectocervical and endocervical cells. However, the sample will not be deemed as unsatisfactory if there is no endocervical component.
8. Record the patient’s name, date of birth and ID number on the specimen vial and any other patient identifiers required by the laboratory.
9. On the pathology request form, note the following:
   1. Patient information.
   2. Cervical screening history and other relevant medical history (including gynaecological history).
   3. Any cervical abnormalities visualised during the cervical examination.
   4. Clearly indicate that the sample was clinician-collected.
   5. Patient’s Aboriginal and/or Torres Strait Islander status.
10. After sample collection, ensure the details of the consultation and procedure are accurately documented in the patient’s clinical record.

Ectropion

• Cervical ectropion is a benign gynecological condition and is regarded as a normal variant that frequently occurs in women of the reproductive age group. 
• cells from the ‘inside’ (single-layered mucus-secreting columnar cells, both ciliated and nonciliated) of the cervical canal, are present on the ‘outside’ of the vaginal portion of the cervix. (cells on the ‘outside’ of the cervix are typically multilayered stratified squamous, non keratinized epithelium)
• since the endocervical cells are more fragile and now exposed to the vaginal environment, they are more vulnerable to injury, for example, during sexual intercourse.
• It occurs due to increased exposure of the cervical epithelium to estrogen.
  •     Adolescents
  •     Pregnancy
  •     Women on hormonal contraception
  •     During the years of menstruation, most commonly seen in the ovulatory phase
• It is diagnosed on routine pelvic examination or pap screening. 
• Cervical ectropion is most commonly asymptomatic.
• In symptomatic cases, females may present with any of the following:
  • Vaginal discharge.
    • It is the most common symptom to manifest. 
    • The vaginal discharge is non-purulent and maybe white or yellow. 
    • The surface area of the mucus-secreting columnar cells is increased; therefore, women with cervical ectropion experience excessive vaginal discharge.
  • Postcoital bleeding.
    • It is seen in 5 to 25 percent of women with cervical ectropion. 
    • The fine blood vessels in the epithelium are torn very easily during sexual intercourse, leading to postcoital bleeding.
  • Cervical ectropion is one of the common causes of vaginal bleeding in the third trimester of pregnancy.
  • Intermenstrual bleeding
  • Dyspareunia
  • Pelvic pain
  • Recurrent cervicitis
  • Backache
  • Micturition disturbances
• Management
• requires no treatment unless the symptoms are affecting the patient’s daily life. 
• First-line treatment
  • discontinuing hormonal contraceptives like oral contraceptive pills, depot medroxyprogesterone acetate, and switching to nonhormonal contraception methods
  • If the symptoms persist, the following treatment can be offered:
    • Cautery 
    • Microwave tissue coagulation. 
    • Boric acid vaginal suppositories can be used to make the pH acidic.

HPV vaccination

• Age:
  • from 9 years of age and onwards
  • The optimal age for HPV vaccination is around 12–13 years prior to exposure to HPV 
  • most effective if the vaccine is given early in adolescence
• Used to be 2 dose schedule
• From 6 February 2023
  • the routine 2-dose HPV vaccine schedule provided to young people aged 12 to 13 years will become a single dose schedule
  • NIP-funded catch-up program extended up to and including 25 years of age (increased from 19 years of age)
• immunocompromised
  • should still receive 3 doses of the HPV vaccine – 0, 2, 6 months
  • funded under the NIP before 26 years of age
  • Severely immunocompromising conditions include:
    • primary or secondary immunodeficiencies (complete or partial deficiencies of B-lymphocyte antibody or T-lymphocytes)
    • HIV infection
    • malignancy
    • organ transplantation 
    • significant immunosuppressive therapy
    • (excluding those with asplenia or hyposplenia)
• MSM
  • HPV vaccine is recommended for men who have sex with men (MSM) of any age who have not previously been vaccinated
• Age >26
  • may benefit from being vaccinated 
  • 3 doses are recommended – 0, 2, 6 months
  • Vaccines need to be purchased via private prescription for people aged 26 years and over, and costs may vary. 
• Vaccines available in Australia
  • 2vHPV Cervarix – HPV types 16 and 18
  • 9vHPV Gardasil – HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58
• Gardasil 9vHPV
  • Registered for use in females aged 9 to <46 years and males aged 9 to <27 years.
  • Recombinant protein particulate (VLP) vaccine containing the major capsid (L1) protein of HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58
• Contraindications and precautions
  • anaphylaxis after a previous dose of any HPV vaccine
  • anaphylaxis after any component of an HPV vaccine
  • anaphylaxis to yeast (for 9vHPV)
  • Pregnancy
    • HPV vaccines are not recommended for pregnant women, due to an absence of evidence of vaccine use in large populations of pregnant women.
  • Breastfeeding
    • can receive HPV vaccines
  • Adverse events
    • Headache , fever
    • nausea
    • dizziness, fatigue
    • Guillain–Barré syndrome – possible very small risk (approx. 1 in 100,000 girls vaccinated) 

Human papillomaviruses 

• are small, non-enveloped viruses with circular double-stranded DNA. 
• They infect and replicate primarily within cutaneous and mucosal epithelial tissues.
• More than 100 HPV genotypes have been fully sequenced. 
• Approximately 40 HPV types specifically infect the anogenital tract
• Pathogenesis
  • HPV requires a breach in the epithelial surface to enter the basal epithelial cells and cause infection. 
  • However, infectious virions are only produced in the terminally differentiated layer of the epithelium.
  • high risk –
  • HPV types 16, 18, 31, 33, 35, 45, 52 and 58 are high risk because they can cause cancer. 
  • The most oncogenic HPV type is HPV-16. This is the most frequent cause of HPV-related cancers.

• High-risk HPV types may cause dysplasias and cancers of the:
  • cervix
  • vulva
  • vagina
  • penis
  • anus
  • oral cavity
  • oropharynx
• Dysplasias may be:
  • low grade — the viral cytopathic effect of HPV infection
  • high grade — precursors to cancer
• Low risk –
  • HPV types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 and 89 are low risk. 
  • These are mostly associated with non-malignant lesions such as genital warts
  • may cause lesions such as:
    • cutaneous warts
    • genital warts
    • respiratory papillomatosis
      • is potentially fatal. It is characterised by multiple warty growths on the mucosal surface of the respiratory tract
• Transmission
  • Anogenital HPV is mainly transmitted through sex. 
  • Less commonly, the virus can be transmitted after intimate non-penetrative sexual contact
  • Perinatal transmission of HPV can result in laryngeal infection in infants. 
  • In rare cases, this can lead to recurrent respiratory papillomatosis.
• Most people clear genital HPV infections (that is, the infection is no longer detectable by HPV DNA testing) within 12–24 months. 
• However, in some cases, the virus is thought to remain as a latent infection even though DNA is no longer detectable.
• In about 3–10% of infections, the virus persists. 
• People with persistent HPV infection are at risk of developing HPV-associated cancers.