 Cervical cancer is the second commonest cancer of women (first is breast cancer)

 80% in underdeveloped world

 75%
o Developed world – early presentation
o Developing world – present in advanced stage
 Deprivation α incidence of cervical cancer

Epidemiology and Aetiology

 HPV, immunosuppresion and Smoking

 Sexually transmitted infection
 Condoms do not protect from infection (infection transmits from skin to skin contact during
intercourse)
 80% of sexually active adults show serological evidence of previous infection. Most of the
infection is cleared within few years, minority will retain the virus in the epithelium and progress
in to CIN/carcinoma
 Smoking contributes as its Nicotine derivatives are immunosuppressive

Pathology

 Occasionally when mucous columnar epithelium is covered by squamous epithelium there is

retention of mucus – nabothian follicle
 Transformation zone is the site where premalignant and malignant develop
 Viral DNA is integrated in to the genome of the basal cells within the epithelium in TZ
 Disordered immaturity with the TZ is called CIN

Natural History of CIN

 Spontaneous regression of low grade disease is not uncommon

 If left untreated 20% patient with high grade abnormalities may develop cancer of the cervix
 Reasons
o Reduced host immunity
o Oncogenic HPV type
o smoking

Screening

 First invitation – 25 years

 25 – 49 years – 3 yearly
 50 – 64 years – 5 yearly
 60+ - those who have not been screened since 50 years

Pap smear and Colposcopy

 Cells exfoliated from the cervix are examined for cytoloigically

 o Pap smear
o Liquid based cytology
 Most cytological smears are normal
 Abnormal smears can show cells in different degrees of maturity (dyskaryosis)
 There is some correlation between smear grade and the degrees of CIN on the cervix, but it is
not totally reliable.
 Sensitivity of cervical smear picking up a woman with CIN is 70% (Slow progression of CIN to
cancer assures picking up women who were missed in subsequent smears)
 Smears act as a means of referring patients to the colposcopy clinic for further assessment

Low Grade Smears – 2%

High Grade Smears – 4%

 CIN 3 – Carcinoma in situ

 Schiller’s Iodine – stain normal glycogen rich epithelium. Fail to stain columnar and abnormal
epithelium
 Green filter – recognize vascular patterns

Colposcopy

 Used for both diagnosis and treatment

 5% Acetic acid – nucleoproteins in the cells coagulate temporality  increase areas of cell
turnover (eg. CIN) will appear white
 Iodine
o Areas of CIN lack glycogen – stain yellow
o Normal epithelium – Stain brown
 Angiogenesis will be seen via colposcopy
 Objectives
o Presence of CIN or Cervical Cancer
 CIN
 Low grade – colposcopy and cytology six months later
 High grade – treat in the clinic same day

Cervical cytology classification

 Bethesda system

Classification

HPV Changes L-SIL (Low Grade Squamous

CIN 1 Intraepithelial Lesion)
CIN 2
HSIL
CIN 3
ASCUS (Atypical Cells of
Undetermined Significance)
Atypical Squamous Cells
ASC-H (Cannot exclude High grade
SIL)
Management of Abnormal Cervical Smear

 Should have a colposcopy assessment

 Aims of colposcopy
o Exclude invasive process
o Identify the extent of abnormality and its likely grade
 Adequacy of colposcopy
o Whole transformation zone should be visualized
o Inadequacy of visualization of transformation zone (up to SCJ) is an indication of
excisional biopsy of transformation zone
 Clinico-Colposcopic Index

CCI Score

 0 – 2 – insignificant lesions
 6 – 10 – High Grade disease
 3 – 5 - histological pattern is mixed
with a tendency of the lesion to
harbor CIN grade 1 or 2.

Treatment of CIN
Ablative and excisional techniques

 > 90% cure rate

 Now not ‘see and treat’ but ‘select & treat’
 Ideal depth of destruction – 5 – 8 mm (eradicate 99.7% cases)
 Cryocautery – relatively increased failure rate
 Maximum of three loops before hysterectomy is considered
 Recognizing the potential for overtreatment has been the main reason why women under 25
are not screened

Ablative Techniques

 Cryocautery
o Depth 4 mm
 Electrodiathermy (GA/LA)
o Needle and ball
o LLETZ
 Cold coagulation
o Via Teflon coated thermasound
o Depth
 2.5 – 4 mm (1000C for 30 s)
 > 4 mm (1200C for 30 s)
 Carbon Dioxide Laser
o Good control of depth destruction
o Good healing
o Excellent haemostasis
o Useful in treating pre-malignant lesions with vaginal involvement

Excisional Methods

o Laser and diathermy loop excision

 Can be used to fashion cone biopsy of cervix
 Success rates similar to laser ablation and cold coagulation
 No adverse effects on fertility
o Hysterectomy/cone biopsy
 Can be used in the presence of other uterine causes for TAH
 Colposcopy used to assess the extension into the vagina (VAIN – Vaginal
Intraepithelial neoplasia)
 Coloposcopic findings can be used to determine the size and shape of the cone
biopsy
  Internal os and endocervical canal is preserved as much as possible
(reduced haemorrhagic tendency and fertility compromise)
 Cervical cytology – good prognostic indicator than excision cone margins for
residual disease
 5% patients develop cervical stenosis/incompetence after procedure

Pregnancy implications

 Excisional method (cold knife cone biopsy, LASER, LLETZ)  preterm delivery/LBW/PROM
 Adverse outcomes α cervical volume and endocervical canal that is removed

Management of abnormal cytology

Treatment Failure
  Primary objective – prevent invasive carcinoma
 Those who undergo treatment of CIN remain at higher risk of invasive disease
 Abnormal cytology following treatment – increased risk
 Those treated for CIN need long term follow up
 Reason for many invasive carcinoma
o Inappropriate selection for treatment
o Failure to recognize early invasive disease at the time of initial assessment
 Cytological abnormality following treatment
o Indication for colposcopic assessment
 Factors causing colposcopic assessment more difficult
o Prior surgery
o Islands of CIN/invasive disease can be buried under an apparently normal epithelium
 Excisional methods should be used in treatment failure

Human Papillomavirus

Cervical cancer is a rare outcome of HPV infection

HPV infection is an STI

HPV infection is found in almost all cases of cervical cancer

Most HPV infections will not progress to CIN/cancer

Persistence HPV DNA is needed for the invasive disease

80 known HPV genotypes

30 infecting the genital tract

20 identified as carcinogenic

Low risk – 6, 11 (90% of anogenital warts), 41, 44

Intermediate Risk – 31, 33, 35 and

High risk – 16, 18 (72% cases), 45, 56

HPV DNA Test – clinical applications

 Primary screening
o HPV testing ± cytology  sensitive > Specific
o Used in women > 30 years
o ARTISTIC Study  combination of HPV test and cytology allows earlier detection of high
- grade lesion
 Triage of minor cytological abnormalities
o ASCUS, LSIL
 o Common in younger females
o These minor abnormalities present a difficult problem in their management
o Considerable proportion have an underlying high grade lesion
o HPV test has a role in triage of those women who need colposcopy
o Significantly better sensitivity and similar specificity for HPV test in comparison to
repeat cytology for the detection of high- grade lesions for ASCUS/borderline cytology
(55% positivity)
o Because of high positivity rate (85%) in low grade group/mild dyskaryosis HPV test
fails as a triage tool
o Compared to cytological surveillance immediate colposcopy detects high grade lesions
in low grade group – TOMBOLA study
 In the follow up after treatment
o HPV test ± cytology  identification of treatment failures
o Can be used as a ‘test of cure’
o HPV test with cytology has high negative predictive value – negative for both at 6
months can safely return for 3 year recall

HPV Vaccination

 Gardasil® - Quadrivalent (HPV 16/18/6/11)

 Cervarix® - Bivalent (HPV 16/18)
 Given ideally for pre-pubertal women before their first sexual intercourse

Non treatment with serial colposcopy for low grade lesions

Cervical cancer presentation

 Asymptomatic
 Post coital bleeding
 Intermenstrual bleeding
 Postmenopausal bleeding
 Offensive blood stained vaginal discharge
 Abnormal bleeding in pregnancy
 Late disease – backache (malignant infiltration of the spinal cord), incontinence (vesicovaginal
fistula), anaemia (from chronic vaginal bleeding), leg pain/oedema, haematuria, bowel changes,
malaise and weight loss, renal failure (from ureteric blockage)

Diagnosis

 History and clinical examination

 Abnormal cytology
 Colposcopic features
o Intense aceto-whiteness
o Atypical vessels
o Raised/ulcerated surface
 o Contact bleeding
o Atypical consistency bimanual examination
 Wedge/cone biopsy
 Some tumours are endophytic rather than exophytic and therefore clinically less revealing


Staging

 Clinical
 Stage Ib or worse should have a chest CXR and IVU
 Look for obstructive uropathy
 EUA with combined rectovaginal assessment
 Rectovaginal examination under anaesthetic
o size of disease,
o fixity
o vaginal involvement
 Biopsy of the suspicious area
 Cystoscopy should be considered
 CXR/IVU
 Sigmoidoscopy
 CT/MRI

Extended to lateral pelvic

Confined to the Cervix
0 – carcinoma in situ,
intraepithelial carcinoma
I – carcinoma is strictly
confined to the cervix
(extension to the corps
should be disregarded)
Microscopic Lesions
IA – invasive carcinoma
which can be identified only
by microscopy, with deepest
invasion ≤ 5 mm and largest
extension ≤ 7 mm
Beyond the Uterus, Not in
Pelvic Wall/lower third of
the vagina
II – Cervical carcinoma
invades beyond the uterus,
but not to
the pelvic wall or to the
lower third of the vagina
IIA – Without parametrial
invasion
IIA1 - Clinically visible lesion
≤ 4.0 cm in greatest
dimension
wall/lower third of
vagina/hydronephrosis/non
functioning kidney
III – The tumour extends to
the pelvic wall and/or
involves the
lower third of the vagina
and/or causes
hydronephrosis
or non -functioning kidney
IIIA – Tumour involves lower
third of the vagina, with no
extension to the pelvic wall
IIIB – Extension to the pelvic
wall and/or hydronephrosis
or
non-functioning kidney
Extended beyond true
pelvis/involvement of
bladder or rectal mucosa
IV – The carcinoma has
extended beyond the true
pelvis or
has involved (biopsy proven)
the mucosa of the bladder
or rectum. A bullous
oedema, as such, does not
permit
a case to be allotted to stage
IV
IVA – Spread of the growth
to adjacent organs
IVB – Spread to distant
organs
 IA1 – Measured stromal IIA2 – Clinically visible lesion
invasion of ≤ 3.0 mm in > 4.0 cm in greatest
depth and dimension
extension of ≤ 7.0 mm
IA2 – Measured stromal IIB – with obvious
invasion of > 3.0 mm and parametrial invasion
not > 5.0 mm
with an extension of not >
7.0 mm
Clinically Visible
Lesions/Preclinical lesions >
IA
IB – Clinically visible lesions
limited to the cervix uteri or
preclinical cancers greater
than IA
IB1 – Clinically visible lesion
≤ 4.0 cm in greatest
dimension
IB2 – Clinically visible lesion
> 4.0 cm in greatest
dimension

Survival

Survival is stage specific

Volume of disease has a major influence on outcome

Stage 5 year survival

I > 95%
II > 50%
III > 40%
IV > 5%

Histoloy

 Squamous type – 80 – 85%

 Adenocarcinoma element – 15 – 20%
 Adenocarcinomas are less likely to be picked up from cervical screening
 Rare types – clear cells, lymphomas, sarcomas

Pathophysiology

 Tumours are locally infiltrative

 Spread via lymphatics and in late stages via blood
 Tumours can grom through cervix to reach the parametria (anatomical are lateral to cervix),
bladder, vagina and rectum
  Metastases can occur therefore in pelvic (iliac and obturator) and para-aortic nodes and, in the
later stages, liver and lungs.

Management

 Options
o Surgery
o Chemotherapy
o Radiotherapy
o Combined therapy
 Groups
o Curative
o Palliative
 Early stage – curative intention with surgery and radiotherapy
 Late stage – chemotherapy
 Small mobile tumours favour surgical approach
 Larger fixed tumours favour radiotherapy

Cervical Cancer

Clinical Staging

Stage IA Stage IB1 Stage IB2, IIA - IV

Conservative Assess nodal status Chemoradiation

Surgery laparoscopically

Node Negative Node Positive

Radical Chemoradiation
Hysterectomy

Radical
Trachelectomy

Stage IA
  Breaches the basement membrane – but rarely associated with metastasis
 Management option
o Simple hysterectomy
o Cone biopsy – if fertility wishes present
 Margins of the specimen should be checked for CIN or invasive disease
 Risk of distant disease
o IA1 - < 1%
o IA2 - < 5%
 Tumor volumes < 420 mm3 have virtually no risk of metastasis

Stage IB1

 Options
o Radical surgery (radical hysterectomy {removal of cervix, upper third of vagina, uterus
and parametrail tissue} with bilateral pelvic lymphadenectomy ± oophorectomy) –
Wertheim’s Hysterectomy
o Pelvic lymph nodes – obturator, internal and external iliac
o Radical radiotherapy
 Problems after surgery
o Bladder dysfunction (atony)
o Sexual dysfunction
o lymphoedema
 Surgery for young women
o Preserve the ovaries
o Reduces the risk of sexual dysfunction
o not associated with the late sequelae of radiotherapy
 5 year survival
o Node negative patients – 90%
o Node positive patients – 46%
 Radical Radiotherapy
o where surgical expertise is not available
o Not medically fi t for surgery
 Aims of radical radiotherapy
o Treat primary tumor
o Treat lymphatic spread
 Radiotherapy
o Intracavitary (intracavitary brachytherapy) – for primary tumour
 Delivered internally to the patient
 Radiation source is Selenium
 Rods are inserted into the uterus and connected to the radiotherapy source
 Harmful effects on bladder and bowel are minimized by limiting the area to 5
mm from rod
o External beam therapy
 Radiation is delivered from a distant to the patient
  From linear accelerator
 pelvic lymph nodes
 usual dose is around 45 Gy (Grays) – given in fractions
o side effects
 lethargy
 bowel and bladder urgency
 skin erythema
 5% will experience serious side effects (bowel perforation)
 Vaginal stenosis
 Bladder damage – cystitis-like symptoms, haematuria
 Bowel damage – malabsorption, mucous diarrhea

 Adjuvant chemotherapy
o Cisplatin
o Enhance the effects of chemotherapy
o Address micrometastases
o lymph node spread
o Tumor at the excision margins
o Other risk factors that make a recurrence likely
 Ovarian Involvement
o Squamous cell cancers - < 1%
o Adenocarcinoma – 5 – 10%

Stage IB2 – IVA

 Chemotherapy is preferred (Specially those advanced locally)

 Cisplatin based chemotherapy in conjunction with radiotherapy
 Radiotherapy – Curative or palliative

Stage IVB

 No standard therapeutic protocol

Minimal Access Surgery

 To assess the lymphatic spread at the time of diagnosis

 Lymph node yield at laparoscopy is equivalent to open approach
 Node negative – surgical cure is feasible, proceed with radical or fertility sparing surgery
 Node positive – chemotherapy
 Radical surgeries can be performed using minimal access methods

Fertility sparing surgery

 Radical trachelectomy
o Removing the cervix, parametrium and upper third of the vagina in those with
histologically negative pelvic lymph nodes
o Cervical circlage is inserted in future pregnancy
Recurrent cervical cancer

 Should be referred to the expertise in managing the disease

 In cases of pelvic recurrence a previously not used modality should be used
 Radiotherapy is used generally
 Radiotherapy failures are treated with pelvic exenteration in fit candidates
 PET-CT is used to exclude distant metastatic disease

Cervical cancer in pregnancy

 Abnormal bleeding is the presentation

 20% are asymptomatic
 Route of delivery does not affect the 5 year survival
 Cone biopsy results in excessive bleeding
 Indications for cone biopsy
o Pap smear suspicious of invasive cancer with no colposcopic proof
o Colposcopic suspicion or directed biopsy indicating an invasive lesion
 Before 24 weeks treatment is same as those non pregnant
 Radiotherapy (external beam therapy) in T1 – Abort
 In T2 foetus must be surgically removed before treatment
 Radical hysterectomy and pelvic lymphadenectomy can be accomplished at any gestational age
 When with foetal viability  radical caesarean hysterectomy is performed
 Route of delivery  CS

Pathology

 High risk HPVs (16 & 18) are implicated as the most important factor
o HPV – 16 – 60% of Cancers
o HPV – 18 – 10% of Cancers
o Other HPV strains 5% of cases
 High risk HPV strains are also associated with squamous cell carcinomas of vulva, vagina, penis,
anus, tonsil and other oropharyngeal locations
 Cervical HPV infections are extremely common, mostly asymptomatic, do not cause any tissue
changes (PAP test is negative)
 50% of HPV infections are cleared within 8 months and 90% within 2 years
 High risk HPV infections last longer than low risk infections
 Persistent infection increases the risk of development of cervical precursor lesions

Pathogenesis

 HPVs infect immature basal cells of the squamous epithelium in areas of epithelial breaks, or
immature metaplastic squamous cells present at the squamocolumnar junction
  HPV cannot infect the mature squamous cells (ectocervix, vagina and vulva)
 Infection requires damage to the surface epithelium
 Cervical cancer in women and anal cancer in homosexual men are common due to this reason
(Anal-Rectal Transformation Zone (transitional epithelium) undergo metaplastic changes)
 E6 and E7 viral proteins interfere with the activity of tumour suppressor genes
 HPV infects mature squamous cells  viral replication occur in mature cells
 Normally mature squamous cells arrest in G 1 phase of cells cycle  HPV infection causes them
to actively progress through cell cycle  HPV uses cell’s DNA synthesis machinery to synthesize
its viral genome
o Cause cell to progress through cell cycle
o Impairs the cells ability to repair DNA damage
 Factors determine progression to cancer
o Exposure to co-carcinogens
o Host immune status
o Regression or persistence of HPV infection

Cervical Intraepithelial Neoplasia (Squamous Intraepithelial Lesion)

Dysplasia/Carcinoma Cervical Squamous

In Situ Intraepithelial Intraepithelial Lesion
Neoplasia (CIN) (SIL), Current
Classification
Mild Dysplaisa CIN I Low-grade SIL (LSIL)
Moderate Dyplasia CIN II High-grade SIL (HSIL)
Severe Dysplasia CIN III High-grade SIL (HSIL)
Carcinoma in situ CIN III High-grade SIL (HSIL)

 LSIL (Not premalignant)

o associated with a productive HPV infection
o high level of viral replication
o mild alterations in the growth of host cells
o does not directly progress to invasive carcinoma
o small percentage progress to HSIL
 HSIL
o Progressive deregulation of the cell cycle by HPV
o Increased cellular proliferation
o Decreased or arrested cellular epithelial maturation
o Lower rate of viral replication
o Derangement of the cell cycle (may become irreversible)
o High risk for progression to carcinoma
 LSIL 10 times more common than HSIL

SIL
  Koliocytic Atypia
o Nuclear atypia
 Nuclear enlargement
 Hyperchromasia (Dark staining)
 Coarse chromatin granules
 Variation in nuclear size and shape
o Cytoplasmic halos
 SIL grading
o Based on the expansion of the immature cell layer from its normal, basal location
o LSIL – immature cells are confined to the lower one third of the epithelium
o HSIL – immature cells expand to the upper 2/3 of the epithelium
 Histologic features of LSIL correlate with HPV replication and changes in host cell growth and
gene expression
 80% LSILs and 100% HSILs are associated with HPV infection
 HPV-16 is the most common type in both LSIL and HSIL
 Majority of HSILs develop from LSILs
 20% of HSILs develop de novo

Progression of lesion in 2 years follow up

Lesion Regress Persist Progress

LSIL 60% 30% 10% to HSIL
HSIL 30% 60% 10% to carcinoma

Cervical Carcinoma

 Average age – 45 years

 Squamous cell carcinoma – 80%
 Adenocarcinoma – 15%
 Adenosquamous and neuroendocrine carcinomas – 5%

Clinical features
 Microinvasive disease – cervical cone excision
 Invasive disease – hysterectomy with lymph node dissection
 Advanced disease – radiotherapy and chemotherapy

Prognosis
 Small neuroendocrine cells – poor prognosis
Survival rates 5 years
 Microinvasive carcinoma 100%
 Tumours extending beyond pelvic < 50%
Most patients die due to consequences of local tumour invasion
 Ureteral obstruction
 Pyelonephritis
 Uraemia