Cervical Intraepithelial Neoplasia (CIN) and Cervical Cancer

Question 1

Describe the anatomy of the cervix
(location and function)

Answer 1

• The lower, narrow part of the uterus which separates it from the upper part of the vagina- approximately 3cm long and 2.5cm wide
• Function- A barrier between the vagina and uterus, acts as a ‘sphincter,’ supporting the weight of the uterus during pregnancy
• Consists of an internal (opening into the uterus) and external (opening into the vagina) os

Question 2

Where is the endocervix, what cells make it up and what is its function

Answer 2

• Between the internal and external os is the ENDOCERVIX
• Consists of a short narrow canal lined with columnar epithelium which produces mucins
• The endocervix canal allows menstrual products to escape during menstruation and allows sperm to enter the uterus
• Endocervix has deep crypts which are lined by columnar epithelium

Question 3

Where is the ectocervix, what cells make it up and what is its function

Answer 3

• The part of the cervix which projects into the vagina (continuous with vagina)- it can be visualised on the speculum.
• Lined with non-keratinised stratified squamous epithelial cells
• Intermediate and superficial cells contain glycogen

Question 4

What is the squamocolumnar junction (SCJ)

Answer 4

• The meeting of these two types of epithelial cells (between ectocervix and endocervix)
• The SCJ has varying positions through life (in children- lies in the external cervical os, extends outwards at puberty to the ectocervix, then returns to the external os in adulthood via metaplasia)

Question 5

What is the transformation zone

Answer 5

• The area between the original SCJ and current SCJ where the epithelium has changed from columnar to squamous epithelium over time (physiological process caused by acidity of vagina, which increases risk of dysplasia)
• This is the site where malignancy and pre-malignancy are most likely to develop. ALmost all cervical cancer origionates from the ecto or endocervical mucosa in the transformation zone.
• Women exposed to high levels of oestrogen e.g. teenagers, pregnant women, those on COCP, may develop a CERVICAL ECTROPION

Question 6

Definition of cervical intraepithelial neoplasia (CIN)

Answer 6

A premalignant condition defined by presence of atypical cells within the squamous epithelium

Question 7

Histology of CIN

Answer 7

• Cells are dyskaryotic, exhibit large nuclei (increased nuclear: cytoplasmic ratio) and frequent mitoses
• Typically presents initially in the basal layer of the transformation zone in the immature squamous epithelium present there

Question 8

What is the cause of CIN

Answer 8

• CIN is typically caused by persistent infection with human papillomavirus (HPV), especially the high risk strains (HPV 16,18,31,33,45). Examples of low risk HPV include 6,11,13 (cause benign warts)
• HPV 16 and 18 are detected in >70% of cervical malignancies. As well as 40-50% of vulval and 70-80% of anal cancers
• HPV is a sexually transmitted infection
• Most people have an infection of no consequence (90% of patients clear the virus within 5-10 years post infection), however, premalignant, and malignant change may develop in patients who are unable to clear the infection.

Question 9

Risk factors for CIN

Answer 9

COCP, smoking, immunocompromised, lack of vaccination (should be given before first sexual contact- does not help in established CIN), multiple sexual partners, early first intercourse, high parity (squamous cell carcinoma)

Question 10

Pathophysiology of HPV infection

Answer 10

• HPV enters immature squamous cells of the transformation and integrates its DNA into host DNA- using host DNA it then produces large amounts of the E6 and E7 proteins
• E6 and E7 are responsible for pushing mature squamous cells through cell replication cycle by blocking the action of tumour suppressor genes (p53 and RB)
• The resultant cells are immortalised (resistant to apoptosis) and have a rapid cell turnover
• CIN can regress or progress (low-grade disease is more likely to regress.) High-grade disease is more likely to require treatment.

Question 11

How is CIN graded

Answer 11

• CIN is graded depending on how deep the cell changes go into the surface of the cervix
• CIN1 (also referred to as low-grade squamous intraepithelial lesions)- one-third of the thickness of the surface layer of the cervix is affected
• CIN2- two-thirds of the thickness of the surface layer of the cervix is affected
• CIN3 (sometimes referred to as high-grade or severe dysplasia or ‘stage 0 cervical carcinoma in situ’) the full thickness of the surface layer is affected
• CIN1 lesions are morphological correlates of HPV infections.
• CIN2/3 lesions (collectively referred to as CIN2+) are correlates of cervical pre-cancers that, if left untreated, may progress to cervical cancer

Question 12

Peak age of incidence of CIN

Answer 12

90% of cases of CIN III are women under the age of 45, with a peak incidence of 25-29 years

Question 13

Prognosis of CIN

Answer 13

If untreated, around 33% of women with CIN2+ will develop cervical cancer over the next 10 years (CINI has the least malignant potential and commonly regresses spontaneously)

Question 14

Who is cervical screening available to. How often are women screened and how successful is it.

Answer 14

In England, cervical screening is available to women and people with a cervix who are aged 25-64 years
* Age 24.5 years- first invitation is issued to ensure that the screening test can be completed by their 25th birthday
* Age 25-49 years- recall every 3 years
* Age 50-64 years- recall every 5 years

People aged 65 years of age or older are invited if:
* A recent cervical cytology sample is abnormal
* They have not had a cervical screening test since 50 years of age and they request one

Since the programme was introduced, the number of women dying from cervical cancer has halved (saves around 4500 lives every year in England)

Question 15

What does cervical screening involve

Answer 15

• Primary HPV screening- to identify individuals who have high-risk HPV
• Liquid-based cytology (if hrHPV is found)- to detect early abnormalities in the cervix
• Colposcopy- to diagnose CIN and differentiate high-grade lesions from low-grade abnormalities in people with abnormal cytology
• Cervical screening is not a test for cancer

Question 16

How does gender identity affect cervical screening

Answer 16

Every person who has a cervix and is within the screening age range of 25-64 years is eligible for NHS cervical screening regardless of their gender identity:
* Transgender man still registered as a female or intermediate who has a cervix
* A transgender man registered as a male who has a cervix cannot be invited for screening by the national programme as current cervical screening IT systems do not have the facility to include people registered as ‘male’
* Screening invitations should be made either by his GP practice or the healthcare team managing his gender reassignment
* A non-binary person must also be invited by the GP practice since IT systems are similarly unable to record the gender category of ‘non-binary’
* A transgender woman is ineligible for screening as she as no cervix

Question 17

What are some disadvantages of cervical screening, when are results available after screening

Answer 17

• Must be mindful of disadvantages of cervical screening including- over-diagnosis, psychological distress, pain, discomfort, false reassurance
• The results should be sent within 14 days of the sample being taken.

Question 18

When should cervical screening be delayed

Answer 18

• If the woman is menstruating, is less than 12 weeks post-partum, is less than 12 weeks after TOP or miscarriage, is pregnant or has vaginal discharge/ pelvic infection.
• If a person has been called for routine screening and she is pregnant, the test should be deferred for when she is at least 3 months post-partum
• If a previous screening test was abnormal and in the interim the person becomes pregnant, colposcopy should not be delayed.

Question 19

Next steps in patients who test positive for hrHPV

Answer 19

Should have a cytology test performed:
* People who are hrHPV positive and receive a negative cytology report should have the HPV test repeated at 12 months
* If HPV testing remains positive at 12 months, the person should have a repeat HPV test in a further 12 months
* If HPV testing remains positive at 24 months, the person should be referred to colposcopy

Question 20

What might cervical samples show on cytology

Answer 20

Negative — no abnormality is detected.

Abnormal — the cervical samples may show:
* Borderline changes in squamous or endocervical cells.
* Low-grade dyskaryosis.
* High-grade dyskaryosis (moderate).
* High-grade dyskaryosis (severe).
* Invasive squamous cell carcinoma.
* Glandular neoplasia.

Inadequate — this may be because the cervical sample:
* Was taken but the cervix was not fully visualized.
* Was taken in an inappropriate manner (for example, using a sampling device not approved by the NHS Cervical Screening Programme).
* Contains insufficient cells.
* Contains an obscuring element (for example, lubricant (cannot use on speculum), inflammation, or blood).
* Was incorrectly labelled.

Question 21

Describe the process of colposcopy

Answer 21

• Colposcope (magnifying device) is used to examine the cervix with a light source
• If acetic acid is applied to the cervix, abnormal areas (such as CIN- increased cell turnover areas) tend to turn white (sometimes referred to as acetowhite).
• Other things to assess include- vascular pattern, surface contour, sharp line of demarcation
• o If an iodine solution is applied, normal tissue (on the outside of the cervix) stains dark brown. Pre-cancerous abnormalities may not stain with iodine. The cells on the inner part of the cervix do not stain brown
• Areas of CIN lack intracytoplasmic glycogen
• If colposcopy testing is adequate and negative- should be followed up in the community at 12 months (if HrHPV testing is negative at 12 months, the individual Is returned to routine recall)

Question 22

What should be done if cytology is inadequate

Answer 22

• The sample should be repeated in no less than 3 months UNLESS it is a 24 month repeat test, then refer for colposcopy
• Individuals who have two consecutive HPV results which are unavailable or inadequate are referred to colposcopy

Question 23

Risk of developing cervical cancer after treatment for CIN

Answer 23

• Between 2-5x more likely than the general population to develop cervical cancer
• Should be followed up for a test of cure 6 months after treatment

Question 24

How can CIN be managed

Answer 24

Goal of management is to prevent progression to invasive cervical cancer
60% of CIN1 regresses spontaneously, SO repeat smear in 1 year

There is no obviously superior conservative surgical technique for treating and eradicating CIN, however, ablative techniques are only suitable when:
* The entire transformation zone is visualised
* No evidence of glandular abnormality
* No evidence of invasive disease
* No major discrepancy between cytology and histology

If there are moderate to severe abnormalities- can excise OR ablate the region
* Excision- LLETZ (large loop excision of the transformation zone), involves removal of abnormal cells using a wire loop that is heated by electric current- specimen is then diagnosed histologically. Depth varies depending on CIN type- must be minimum of 7mm (CINI) and 10mm for CINII
* LLETZ procedure is associated with increased risk of midtrimester miscarriage and preterm delivery
* Cone biopsies can also be done
* Any treatment requires test of cure 6 months later

Question 25

What are the common types of cervical cancer

Answer 25

* **Squamous cell carcinoma**- accounts for 70-80% of cases * **Adenocarcinoma**- accounts for 20-25% of cases (less likely to be picked up on screening since precursor is **cervical glandular intraepithelial neoplasia** CGIN)

Question 26

How can cervical cancers spread

Answer 26

* Cervical tumours are locally infiltrative in the pelvic area but also spread via lymphatics and in late stages via blood vessels * Can grow through the cervix to reach the parametria (anatomical area lateral to the cervix), bladder, vagina and rectum * Sites of metastasis: **pelvic lymph nodes, para-aortic nodes, liver, lungs**

Question 27

How do we define persistant hrHPV infection

Answer 27

‘Persistent infection’ describes the presence of the same type-specific HPV DNA on repeat sampling **after 6-12 months**. Around 90% of incident HPV infections are short-lived and resolve spontaneously within 2 years

Question 28

What is the time course of HPV infection to precancerous and cancerous lesions

Answer 28

The time interval between HPV infection and development of precancerous lesions is **1-10 years**, progression to invasive carcinoma is usually **more than 10 years**.

Question 29

Incidence of cervical cancer. Peak age of incidence

Answer 29

Incidence: Cervical cancer is the **14th most common cancer in females** in the UK (accounts for 8% of cancers diagnosed in women worldwide), with around 3200 new diagnoses every year (1 in 142 females) * Incidence is highest in females **aged 30-34 years** * Cervical cancer is **rare in people aged under 25 years**, despite cervical abnormalities being common in this age group. * There is an estimated relative reduction in cervical cancer of 34% for vaccine offered at age 16–18 years, 62% for 14–16 years, and 87% for 12–13 years compared with a reference unvaccinated cohort

Question 30

Complications of cervical cancer

Answer 30

Psychosocial, sexual dysfunction (often related to radiotherapy treatment, nerve damage during surgery or postoperative pain), early menopause and loss of fertility (associated with management), bladder and bowel dysfunction.

Question 31

Presentation of cervical cancer

Answer 31

* Often **asymptomatic in its early stages,** many cases are diagnosed through the NHS cervical screening programme * Persistent **unexplained abnormal vaginal bleeding**, **intermenstrual bleeding**, and/or **postcoital bleeding** which is not secondary to infection * Unexplained persistent **vaginal discharge** (may be blood stained) * **Pelvic pain** and/or **dyspareunia** * Postmenopausal bleeding and not taking HRT * Abnormal appearance of the cervix on examination, such as inflamed or friable appearance with contact bleeding. May be a visible *ulcerating or necrotic lesion* on the cervix * Rarely, women may present with advanced cancer with such symptoms as pelvic discomfort or pain, renal failure, leakage of urine or faeces from a fistula, lymphoedema, severe haemorrhage, fatigue, weight loss

Question 32

Investigations for suspected cervical cancer

Answer 32

* DO NOT arrange an unscheduled cervical smear if a woman has clinical features of cervical cancer * **2-week wait urgent referral** for colposcopy/ gynaecology oncology assessment should be arranged (DO NOT deferral refer if a woman is pregnant) * Other initial assessment may include: **Punch or excisional biopsy** procedures such as **electrosurgical excision** * MRI of abdomen and pelvis allows staging. Sentinel node biopsy and PET/CT may be needed to check for lymph node involvement and distant metastases. Examination under anaesthesia (EUA) may be needed in some cases to gain tissue for diagnosis and to assess for vaginal or parametrial extension. Can do a cystoscopy for bladder involvement

Question 33

How is cervical cancer staged

Answer 33

Classified according to the FIGO staging system: **Stage 1:** The carcinoma is strictly **confined to the cervix** (excision to the uterus should be disregarded) * 1A- can be visualised on microscopy * 1A1: Measured stromal invasion of more than 3mm in depth, and extension of not more than 7mm * 1A2: Measured stromal invasion between 3mm and 5mm in depth, and extension of not more than 7mm * 1B- may be visible lesions confined to the cervix (greater in size than 1A) * 1B1: Lesions not more than 4cm in size * 1B2: Lesions more than 4cm in size **Stage 2**: The carcinoma extends **beyond the uterus**, but has *not* extended onto the pelvic wall or to the lower third of the vagina * 2A- Involvement of up to the upper 2/3 of the vagina- no obvious parametrial involvement * 2A1: Lesions not more than 4cm in size * 2A2: Lesions more than 4cm * 2B- Obvious parametrial involvement **Stage 3**: The carcinoma has extended **onto the pelvic sidewall**. There is no cancer free space between the tumour and the pelvic sidewall on rectal examination. Tumour has extended to the **lower 1/3 of the vagina**. Concomitant hydronephrosis or non-functioning kidneys should be included * 3A- Involvement of the vagina but no extension onto the pelvic sidewall * 3B- Extesion onto the pelvic sidewal, or hydronephrosis/ non-functioning kidney **Stage 4**: Carcinoma as extended beyond the true pelvis, or has clinically involved the mucosa of the bladder and/or rectum * 4A- Spread to adjacent pelvic organs. * 4B- Spread to distant organs.

Question 34

How can cervical cancer be prevented

Answer 34

* Encourage women to participate in the NHS cervical screening programme, which is available between the ages of 25-64 * Encourage girls aged 12-13 years to receive **immunisation with the HPV vaccine** (for optimum effectiveness, must be given begore the girl becomes sexually active) * Advise girls and women who are sexually active about the importance of using **additional barrier methods** of contraception such as condoms, to reduce the risk of HPV infection.

Question 35

Who should be involved in the management of cervical cancer

Answer 35

Specialist management of confirmed cervical cancer is undertaken by a multidisciplinary team, which may include gynaecology oncologists, general gynaecologists, clinical oncologists, radiologists, and clinical nurse specialists

Question 36

How should stage 1 cervical cancer be managed

Answer 36

**Stage 1A1** (microinvasive disease): * Loop electrosurgical excision with negative margins to cancer and dysplasia * *Simple* hysterectomy (if no need for preserved fertility) **Stages 1A2-1B2** (early-stage disease): * **Radical hysterectomy** (resection of the cervix, uterus, parametria and cuff of the upper vagina) **and bilateral salpingectomy** and/or bilateral oophorectomy with bilateral pelvic lymphadenectomy * Risks include- bladder dysfunction (atony), sexual dysfunction, lymphoedema * The woman may be *considered for adjuvant chemotherapy or radiotherapy* if immediate or high risk or recurrence depending on size (>4cm), position etc.

Question 37

How should stages 2-4A cervical cancer be managed

Answer 37

* Treatment with external beam radiotherapy, intracavity brachytherapy (radiation source placed in the uterus and vagina), and concomitant chemotherapy (cisplatin) is usually used first line to reduce recurrence risk, increase chance of cure, and prolong life * Risks include lethargy, bowel and bladder urgency skin erythema, fibroids, malabsorption, menopause * Surgery is **not recommended** as it is unlikely to be curative

Question 38

Management of stage 4B cervical cancer

Answer 38

Systemic chemotherapy usually given first line

Question 38

Prognosis of cervical cancer

Answer 38

* 96% of women will survive for 1 year or more when diagnosed at stage I * 50% of women will survive for 1 year or more when diagnosed at stage IV In general * 81.1% of women survived for 1 year or more. * 61.4% of women survived for 5 years or more. * 51.2% of women survived for 10 years or more