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Cervical cancer

Dr. L. Mihalcean
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. 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
Cervical 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 2/3s of the epithelium
Approximately 50% of CIN 2 cases will
regress within 2 years
CIN 3 Severe dysplasia affects greater than
2/3s of the epithelium, may affect the full
thickness
CIN 3 - 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 Lugols solution, or , Schillers 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 ofpremature 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 / hysterectomy now 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 wont 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 Usually the result of poor Repeat the sample as soon as possible. If
sample sampling technique, but three inadequate samples, the refer for
could just be a difficult colposcopy
case

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)
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 hysterectomy usually 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 vaccina
Women should still attend for smear
screening as norma