Introduction

When we talk about cervical cancer, we are normally referring to squamous cell carcinoma.
Cervical cancer is a bit complicated. There are normal physiological changes that occur to the cervix, as well as pre-cancerous changes, and cervical cancer itself, which can alter the appearance and histology of the cervix.

Normal physiological changes

Before puberty, the cervix is lined by squamous epithelium. As you progress up into the os, somewhere along the endocervical canal, the squamous epithelium becomes columnar.
During puberty and also during pregnancy, the squamo-columnar junction (SCJ) will migrate down out of the os, and onto the cervical surface, and can be seen from the vaginal side on speculum examination. This is a normal physiological change and is usually referred to as ectopy.
When the SCJ is in this region, the columnar epithelium is exposed to the low pH of the vagina, and this epithelium will undergo squamous metaplasia. Again, this is a normal physiological change.
The site where the columnar epithelium is undergoing metaplasia is known as the transformation zone.
The term transformation zone, and SCJ refer to a similar part of the cervix, but should not be used interchangeably.

  • Transformation zone – this is a relatively wide area between the SCJ as it was before puberty (i.e. up in the os), and where it was at its lowest point during puberty (i.e. on the cervical surface somewhere. It is the area of cells that undergo metaplasia
  • SCJ – this is the boundary between the columnar and the squamous epithelium. It can move over time – it is in the os before puberty, and migrates down the os during puberty (ectopy), and then migrates back up into the os, after puberty.

After puberty and pregnancy, the SCJ will slowly migrate back up into the cervical os

 
 

Ectopy / cervical ectropion

aka Cervical Erosion
This refers to the state whereby the columnar epiethelium is present on the vaginal surface of the cervix (the ectocervix). It is a normal physiological state for many women after puberty.

On examination – there may be a red looking area around the os, which should not be confused with other conditions such as cervicitis.
It can result in an excess section of mucous, as the columnar epithelium contains mucous secreting glands, thus there can be a large amount of normal physiological mucus.
It may also cause post-coital bleeding, due to the presence of delicate blood vessels in the columnar epithelium.
Factors which increase the risk of cervical ectropion are generally related to those that increases levels of oestrogen:

  • Oral oestrogen containing contraceptive
  • Menstruating age

Treatment – usually not treatment is required, but if it is particularly troublesome, then you could try cessation of the COC, or in serious cases, ablation therapy may be used.

Pre-cancerous changes and HPV
Early stages of cervical epithelial change can be detected with smear testing, and colposcopy (see screening programme below).
  • The cervical metaplasia described above is normal
  • ervical dysplasia is a precancerous change that can occur to the cervical mucosa.
 

HPV

There are >100 types of HPV
It is a single stranded DNA virus that infects squamous epithelium – e.g. repiratory and genitoanal tracts
About 40 types of HPV affect the genital tract
Types of HPV are classed as ‘high risk’  or ‘low risk’ for cervical cancer

  • Types 16 and 18 are high risk
    • Type 16 accounts for 50% of cases of cervical cancer
    • Type 18 accounts for 15-20% of cases of cervical cancer

Most HPV infections are transient and will be cleared by the host immune system – but during the course of the infection there may or may not be signs of CIN (see below).

  • 70% of sexually active females will contract HPV types 16/18 during their lifetime.

CIN – Cervical intraepithelial neoplasia

aka cervical dysplasia/ dyskaryosis
This describes an abnormal growth of the cervical mucosa. It is potentially pre-malignant, but in the vast majority of cases, will resolve normally, with no resulting neoplasia.
  • CIN is almost always the result of HPV infection (nearly always types 16 or 18 (type 16 is more common).
  • Most cases of HPV infection, and thus most cases of CIN will be cleared by the host immune system.
 
 
The process of dysplasia is separate from HPV infection. HPV can be present without dysplasia.

Classification of CIN

The diagnosis and staging of CIN is made on Colposcopy and histology. The diagnosis of dyskaryosis is made on cytology – from a smear sample.

CIN 1 – Mild dysplasia – confined to the basal 1/3 of the epithelium
CIN 2 – Moderate dysplasia – confined to the basal 2/3’s of the epithelium

  • Approximately 50% of “CIN 2” cases will regress within 2 years

CIN 3 – Severe dysplasia – affects greater than 2/3’s of the epithelium, may affect the full thickness

  • Sometimes referred to as Carcinoma in situ
  • 18% at 10 years will become cancerous
  • 36% at 20 years
  • If the CIN progresses, it will progress in a linear fashion through the stages 1,2 and 3
  • If CIN does progress to cervical cancer, then the typical progression takes 15 years, although it may occur in 3-40.
    • Although most cancers will progress through the stages of CIN first, some very high grade neoplasms will not present as CIN first.
    • Time from HPV infection to development of cervical cancer is 10-20 years
  • Lifetime recurrence of CIN is about 20%

Investigations

  • Screening – the vast majority of dysplasia is discovered on smear test screening. If this cytology is abnormal, then patients will be referred for:
  • Colposcopy – using a microscope to observe the cervix during speculum examination. Allows for diagnosis of CIN

Epidemiology of CIN

Most commonly occurs in women aged 25-35 but can occur at any age
Risk factors for CIN

  • Young age commencing sexual activity (<18)
  • Giving birth under 16
  • Multiple sexual partners
  • Immunosuppressant drugs or disease
  • Smoking

Investigations

Smear testing – the level of dyskaryosis can usually be assessed with cytology of a smear sample. Those women with abnormal results will be invited to clinic for colposcopy to further assess the level of dysplasia, and be offered treatment
Colposcopy
Contra-indications

  • Menstruation
  • Sexual intercourse, tampons, vaginal medications within 24h before colposcopy

Before the procedure

  • Simple analgesia (e.g. ibuprofen, paracetomol) is recommended 1 hours before the procedure
  • In colposcopy, the cervix is viewed through a microscope (‘colposcope’) during speculum examination.
  • The appearance of the cervix may appear
  • Two solutions can also be applied to the surface of the cervix to help identify abnormal areas:
  • Acetic acid – a solution of 3% acetic acid is applied to the cervix via cotton wool swab. It will turn areas of dysplasia white. Rapidly dividing tissues have a higher nuclear: cytoplasm ratio. Thus when the acetic acid (vinegar) is applied, the rapidly dividing cells become more reflective, and show up white.
    • This helps to identify the site, size and shape of any dysplastic cells.
    • The greater the intensity of the white reflection, the greater the level of dyskaryosis
  • Iodine solution (aka Lugol’s solution, or , Schiller’s test) – after the acetic acid test, the cervix will usually be washed clean with water, and then the iodine is applied. Iodine is taken up by glycogen – normal vaginal cells have a large supply of glycogen to help provide the energy to fight off infection. thus, squamous epithelium will take up the iodine solution and appear very dark brown.
  • Dysplastic and metaplastic cells – have a lower quantity of glycogen – and will not take up the solution and will appear a yellow / orange colour
  • The test is highly sensitive, but not specific.
  • Areas of HPV infection, without dysplasia, may still appear slightly abnormal, but the abnormalities are likely to be more pronounced if dysplasia is present.

Biopsy

  • Any abnormal areas may be biopsied for histology (more accurate than the cytology of the smear)
  • Usually, local anaesthetic is not needed before a biopsy is taken, but some women may find the whole procedure very painful, and may require analgesia.
  • Analysis of blood vessels
  • The colposcope has light filters, which enable to analysis of blood vessels.
  • Green light – can be used to show up the vessels. Under green light, the red blood vessels will show up black, whilst the cervix will appear lighter.
  • Any areas of abnormal blood vessel formation will be biopsied
 

Silver nitrate

  • This is used usually near the end of the examination and has two purposes. It will:
    • Encourage haemostasis
    • Is bacteriostatic – and thus will help to prevent infection
  • It should not be used before biopsy, as it can alter the results

After the procedure

  • The patient should wear a pad
  • Light spotting / discharge can occur for 3-5 days
  • There may also be dark brown liquid (iodine), green patches (silver nitrate)

Complications

  • Generally uncommon
  • Infection
  • Bleeding
  • Pain

Treatment during colposcopy

Where treatment occurs during the colopsocopy, the clinics are sometimes called One stop clinics – as everything is performed under a single appointment, making it more convenient for the patient, and reducing the risk of DNA, or a patient ‘slipping through the net’ – thus increasing the overall population efficacy of the treatment programme. 
Treatment can either be ablation, or excision. Both have success of >90%. Excision is widely used, whilst ablation is not. Excision allow histological analysis of the sample, and also allows a ‘see and treat’ policy, where women can be treated on their first clinic visit, if the colposcopist recommends that treatment is necessary.
Indications for treatment

CIN

  • Level 1 – usually not treated, and regresses without intervention in the majority of cases. If persistent, (e.g. >1-2y) then treatment may be recommended
  • Level 2-3 – usually treated – most commonly via LLETZ in colposcopy clinic

LLETZ – large loop excision of the transformation zone – aka – LEEP (loop electrosurgical excision procedure).
Used to treat CIN 2 and 3
Usually, local anaesthetic is given first
Essentially, the procedure involves a loop of wire that cuts a dome shaped piece of the cervix away. When a current is passed through the loop, it heats up, and can cut through the cervix. Different loop shapes and electrical power can be used
The excision should be 4-5mm deeper than the affected area – which usually means about an 8mm deep incision
Sometimes, a second pass, with a narrower loop is used to obtain a sample for histology.
Complications

  • Reduced when compared to cold knife cone procedure
  • Bleeding
  • Infection
  • Cervical stenosis / incompetence
  • Rare but significant – as it can affect subsequent pregnancy – e.g. may require c-section, and also increases the risk of premature rupture of memebranes, and preterm delivery.
  • Fertility is not affected

After the procedure

  • Procedure is done in colposcopy clinic
  • Similar to colposcopy (spotting / discharge etc)
  • May be some tenderness for a couple of days
  • Patient can return to normal activities the day after the procedure

Efficacy

  • One study suggested that disease with a depth of <3.8mm was eradicated in 99.7% of cases
  • The 4-5mm excisional boundary is a precaution, as some CIN disease has been known to be >5mm depth.

Other treatments

Laser ablation

  • Good for lesions on the vagina
  • Very accurate – affects on the tissue needed

Cold coagulation

  • Despite the name, a hot probe is used to destroy the affected cells. Treatment is either at 100 or 200’, for 30s. The depth of destruction is not easily measureable, but is always >4mm if 200’ for 30s is used.

Cone biopsy / hysterectomynow rarely used, but still suitable in some cases, particularly when there is other co-existing disease (e.g. fibroids, menorrhagia, prolapse, extension of disease into vagina).

Follow-up of CIN
Women with previous CIN have a higher risk of cervical disease in future.
Efficacy
Both excisional and ablation techniques have an efficacy of around 90-95%
 

Cervical Cancer

Epidemiology

In the UK, thanks to screening, it is less common that endometrial and ovarian cancers, however, survival is poorer than endometrial cancer.

  • Worldwide, it is the second most common female cancer, behind breast.

In the UK, affects 9 per 100 000, with a mortality of 3 per 100 000. There are similar rates in Europe and the US.
Smoking

  • Smoking cessation advice should be offered to all women with CIN / cervical cancer

Aetiology

Risk of cervical cancer is increased with:

  • Number of partners
  • Early age at first intercourse
  • Frequency of intercourse

HPV – human papilloma virus – strongly associated with the disease. This virus will incorporate into the host genome, and cause advanced progression of the cervical epithelium from columnar to squamous. There are hundreds of subtypes, many will be symptomless, whilst others (e.g. types 6 and 11) will cause genital warts. Types 16 and 18 are strongly associated with cervical carcinoma.

  • Viral factors related to HPV 16 and 18 can be found in almost 100% of cervical cancers! Immunity to these viruses is the aim of the HPV vaccine (more info later).

Screening

NHS screening programme began in 1988
It is estimated to have reduced cervical cancer incidence by 90%

  • Estimated to save 4,500 lives per year
  • Now less than 1,00 deaths per year in the UK from cervical cancer

Offered to all women aged 25 – 65

  • Every three years between 25-50
  • Every 5 years between 50-65
  • Age 65+ – offered to those who have not been screened since 50 or who have had recent abnormal smears
  • Used to be offered to all women aged 20-65 – but at age 20, the physiological changes seen in puberty may still be apparent, and thus there was a very high percentage of false positives.

What does it involve?

  • A smear test – usually performed at the GP surgery.
  • If this is abnormal, then the patient will be referred for colposcopy, at which time, treatment can be performed if necessary.

Attendance

  • Roughly 80% of those eligible attend for smear screening
  • Reminders – usually, if one appointment is missed, a second invitiation is sent, then if this is missed, another reminder probably won’t be sent, but whenever the patient attends to GP, it will be flagged that a smear has been missed.

Smear test

Results
Result
Comments
Action
Negative
————-
Inform the patient of the result. Invite any questions. Treat any ongoing infection
Inadequate sample
Usually the result of poor sampling technique, but could just be a difficult case
Repeat the sample as soon as possible. If three inadequate samples, the refer for colposcopy
Borderline
 
Borderline changes in endocervical cells
          Refer for colposcopy
Borderline changes in squamous cells
          Repeat screen within 6 months – most cases will have resolved, and smear will be normal at this stage
          Compare past results – if there are >3 borderline changes within 10 years, Refer for colposcopy.
          Three consecutive normal smears are required before patient can return to the normal screening programme
Mild dyskaryosis
 
Usual practice to refer for colposcopy after one abnormal smear, but acceptable to have two, six months apart before referral.
          60% of cases will ultimately resolve spontaneously by the time of the 2nd smear (within 6 months)
Moderate dyskaryosis
 
Refer for colposcopy
Severe dyskaryosis
 
Refer for colposcopy

 Histology and pathology

  • 80-85% are squamous cell
  • The rest are adenocarcinoma

Presentation of cancer

Often asymptomatic
May present on smear testing, but this is not usually the case
Non-menstrual bleeding – the typical presentation

  • In the early stages, the tumour is a firm mass that will exhibit contact bleeding

In more advanced disease:

  • Post coital bleeding
  • Inntermenstrual bleeding
  • Post menopausal bleeding
  • Offensive, blood stained vaginal discharge
  • Abnormal bleeding in pregnancy – then a cervical lesion needs to be excluded

Very advanced disease

  • Backache
  • Leg pain
  • Oedema
  • Haematuria
  • Bowel changes
  • Weight loss

Investigations

Smear – will show cancerous cells
Colposcopy

  • Atypical vessel structure
  • Intense whiteness with acetate
  • Ulcers /lesions on cervical surface
  • Contact bleeding

Staging

Staging is generally clinical.
  • Anybody with a tumour >1b should have a CXR and IVU (intravenous urogram)
Procedure of staging
  • Examination under anaesthetic, including rectal exam
  • Biopsy of the affected area
  • CXR and IVU
  • Cystoscopy (in selected patients)
  • Sigmoidoscopy (in selected patients)
  • CT / MRI (in selected patients)
Stages
Stage
Description
0
Includes all stages of CIN
I
Confined to cervical mucosa
Ia
Lesion <5mm depth and <7mm diameter
Ib
Lesion confined to cervix, but larger than Ia
II
Extends beyond cervix, and into top 2/3 of vagina but not as far as pelvic wall
IIIa
Extends into the lower 1/3 of vagina. Mass palpable from, but not attached to rectum
IIIb
Extension to pelvic wall on kidney.
IVa
Spread to bladder or rectum
IVb
Distal spread
Note that the staging system does not include reference to lymph node spread. This can occur at any stage, and prognosis is much worse if it is present (e.g. for stage I, without spread, survival is 95% with spread it is around 45%).
  • The volume of the lesion also has a significant effect on outcomes
  • Luckily, most disease presents at stage I or II

Prognosis

Average 5 year survival – 61%

  • Stage I – 79%
  • Stage II – 47%
  • Stage III – 22%
  • Stage IV – 7%

Management

Decide if curative or palliative. Palliative care usually only involve chemotherapy, but may also involve surgery.
Stage Ia
  • Usually managed by simple hysterectomy, or even just cone biopsy in some cases.
  • Cone biopsy used in those who wish to preserve fertility
  • In cases where cone biopsy is used, then all the affected area needs to be excised with a reasonable (4-5mm) margin. Histology should confirm that the margins of the removed area are not cancerous or have CIN – they must be completely normal tissue.
  • Lesions >5mm depth should be considered as stage Ib

Stage Ib

  • Total hysterectomyusually with removal of lymph nodes, and ovaries. Risk of spread to ovaries is low (<1% for squamous cell carcinomas and 5-10% for enocarcinoma)
  • Radiotherapy – suitable for women not fit for surgery. Usually a combination of vaginal and external radiation is used to treat both the primary tumour, and lymph nodes.
    • In trials, both methods are equally effective
  • Adjuvant chemotherapy – usually offered to those with lymph node spread

Stage II-IV

  • Usually chemoradiotherapy, and not surgery. The spread of disease associated with these stages is not suitable for treatment with surgery, and the best chance of cure is with chemoradiotherapy.

HPV vaccination

In 2008, the NHS introduced a vaccination programme against the two strains of HPV associated with the vast majority of cases of CIN and cervical cancer (16 + 18).
  • >99% effective in preventing HPV 16 and 18 infection
  • More effective if given before age of sexual activity
  • Provides protection for at least 6 years – studies have not been long enough yet to prove exactly how long immunity is present for.
  • Types 16 and 18 are responsible for >70% of cases of cervical cancer
Who is eligible?
  • All girls aged 12-13 are offered the vaccine
  • Girls up to the age of 18 who have not been vaccinated are also eligible on request
  • Immunosuppressed individuals may also be recommended for the vaccine – however, in the immunocompromised state, immunity may not develop in response to the vaccine.
Regimen
3 doses, given in the arm or thigh. The vaccine used is Cervarix – which provides protection against HPV types 16 and 18. A rival brand of vaccine also gives protection against HPV 8 and 11, which are common causes of genital warts.
  • 1st dose
  • 2nd dose – at 2 months
  • 3rd dose at 6 months
Contra-indications
  • Should not be given in those who had previous allergy to HPV vaccine
  • Safe for those with egg, nut and yeast allergy
Side effects
About 10% experience side effects
  • Soreness at injection site
  • Myalgia
  • Headache
  • Tiredness
  • Dizzyness
  • Urtricaria (rare)
After the vaccine
  • Women should still attend for smear screening as normal

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