Transcript Screening for cervical cancer

SCREENING FOR CERVICAL
CANCER
THE OBSTETRICS & GYNECOLOGICAL SOCIETY OF BHOPAL
&
AMPOGS RESEARCH PUBLIC WELFARE SOCIETY
BREAST AND GENITAL TRACT CANCER INCIDENCE RATES PER
100,000 FEMALES WORLDWIDE
35
30
25
23.2
21.2
19.3
15.7
17.4
16.6
15
10
5
20.2
19.3
20.1
27.5
24.6
23.3
RATE
20
31.3
28.2
4.8
7.2
7.2
1.3
1.4
1.6
1970
1975
1980
6.5
2.3
7.2
7.6
2.5
2.4
1990
1995
8.3
3.2
0
1985
YEAR
BREAST
CERVIX UTERI
OVARY
CORPUS UTERI
2000
BREAST & GENITAL TRACT CANCER INDIA
CERVICAL CANCER INCIDENCE
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Cervical cancer is the fourth common cancer in women worldwide.
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Cervical cancer is also preventable if precancerous lesions are detected in the early
stages of development. Cervical cancer is also potentially curable with early
detection and appropriate treatment.
>80% women with cervical cancer live in low/middle income countries.
> one fifth of these live in India.
Cervical cancer is usually an asymptomatic slow growing cancer and can be
detected easily in its early precancerous stages. If it is not detected at these early
stages, there is an increased risk of progression of the disease to cervical cancer.
WHO NEEDS TO BE SCREENED
• All sexually active/married women of 30-60 years of age should be
screened for cervical cancer except in the following situations:
• Menstruation
• Pregnancy
• Less than 6 weeks of delivery
• Had hysterectomy done
• Screening to be done every 5 years
UTERINE CERVIX
• Lower fibromuscular portion of
ENDOMETRIUM
MYOMETRIUM
SUPRAVAGINAL CERVIX
PORTIO VAINALIS
INTERNAL OS
CERVICAL CANAL
EXTERNAL OS
VAGINA
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uterus .
Length 3-4cms,
Diameter 2.5cms.
Endocervical canal 6-8mm width.
Endocervical canal (columnar
epithelium) varies in extent
depending on woman’s age,
reproductive, hormonal and
menopausal status.
UTERINE CERVIX
• Stroma
of cervix is composed of dense, fibromuscular tissue through which
vascular, lymphatic, nerve supplies to cervix pass and form a complex plexus.
• Ectocervix
is relatively insensitive, while endocervix has extensive sensory
nerve endings, both sympathetic and parasympathetic.
ECTOCERVIX
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Covered by stratified,
nonkeratinising, glycogen containing
squamous epithelium.
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Opaque, pale pink in colour.
Overall, from basal to superficial
layers, cells undergo an increase in
size and reduction in nuclear size.
ECTOCERVIX
• Intermediate and superficial cells contain
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abundant glycogen in their cytoplasm.
Maturation of squamous epithelium
dependant on estrogen.
Terminal capillaries of subepithelial tissue
arise to form capillary loops, just below
and indenting the epithelium.
It is these capillary loops that are seen on
colposcopy
ENDOCERVIX
• Endocervical canal is lined by columnar epithelium.
• Single layer of tall cells with dark nuclei close to basement membrane.
• It is reddish in colour, as a thin single layer allows underlying
vasculature to
be seen clearly.
cells
ENDOCERVIX
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Columnar epithelium is thrown into
multiple longitudinal folds protruding
into lumen of canal.
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It forms invaginations into substance of
cervical canal forming endocervical
crypts.
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Gives grainy appearance on visual
inspection.
ENDOCERVIX
• Glycogen and mitosis are absent in
columnar epithelium.
• Terminal vessels of columnar
epithelium consists of inter twining
capillaries, forming a multi channel
network.
SQUAMOCOLUMNAR JUNCTION
• SCJ appears as a sharp line with a step, due to difference in height of
squamous & columnar epithelium.
• Location of SCJ in relation to external os is variable & depends on age,
hormonal status, birth trauma, OCP’s use, pregnancy.
SQUAMOCOLUMNAR JUNCTION
• Original SCJ visible during premenarche is
located at or close to external os.
• After puberty & during reproductive life the
cervix swells enlarges, endocervix
elongates, leading to eversion of columnar
epithelium on the ectocervix (ectropion).
• Thus original SCJ is located far from
external os.
RESERVE CELLS
SQUAMOCOLUMNAR JUNCTION
• Ectropion prominent in pregnancy.
• The everted columnar epithelium is exposed to high vaginal acidity, leading to
destruction of cells
Proliferation of subcolumnar reserve cells
Reserve cell hyperplasia.
SQUAMOCOLUMNAR JUNCTION
Immature metastatic squamous epithelium.
Normal glycogen containing mature squamous epithelium.
Immature squamous epithelium
SQUAMOCOLUMNAR JUNCTION
Immature metastatic squamous epithelium
Infection with oncogenic virus HPV types.
Atypical or dysplastic squamous epithelium.
Immature
Metastatic
Squamous
epithelium
Mature
Metastatic
Squamous
epithelium
Original
Squamous
Epithelium.
TRANSFORMATION ZONE
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Region of the cervix where columnar epithelium
has been replaced and/or is being replaced by
new metastatic squamous epithelium.
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Its the area of cervix, bound by original SCJ at
distally & metastatic SCJ proximally.
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In premenopausal women the TZ is fully located
on ectocervix.
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After menopause cervix shrinks & TZ may move
partially or fully into cervical canal.
TRANSFORMATION ZONE
• Normal TZ is composed of immature &/or
crypt
mature squamous metaplasia along with
intervening areas or islands of columnar
epithelium with no signs of cervical
carcinogenesis.
• Abnormal or atypical TZ evidence of
cervical carcinogenesis such as dysplastic
change .
TZ
HARALD ZUR HAUSEN
HUMAN PAPILLOMAVIRUS (HPV)
• Double stranded circular DNA molecule.
• Long known to cause warts
• Found in many cancers too
• Over 100 types identified
• Most benign, but 15-20 can cause
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cancers
Very common
• 20,000,000 current cases in US
• 6,200,000 new cases annually
• 80% of women have HPV by age 50
• 50% of college students are infected
HPV & CERVICAL CANCER
• HPV recognized as the underlying cause of cervical cancer since 1996
• NIH Consensus Conference on Cervical Cancer, 1996
• World Health Organization/European Research Organization on Genital
Infection and Neoplasia, 1996
COMMON HPV TYPES AND THEIR EFFECTS
HPV Types
Low-Risk
HPV 6, 11, 40,
42, 43, 44, 54,
Lead to:
Benign cervical changes
Genital warts
61, 70, 72, 81
High-Risk
HPV 16, 18,
31, 33, 35, 39,
45, 51, 52, 56,
58, 59, 68, 73, 82
1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.
2. Munoz et al. N Engl J Med. 2003;348:518.
Precancer cervical changes
Cervical cancer
Anal and other cancers
Human Papillomavirus
 Cancer of cervix
100%
 Cancer of anus
90%
 Cancer of vulva, vagina
40%

Cancer of penis
40%

Cancer of throat

Cancer of mouth

Cancer of esophagus

Cancer of skin

Cancer of X,Y,Z….
Parkin DM et al. CA Cancer J Clin 2005; 55:74-108.
12%
3%
.
.
.
PATHOGENESIS
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There are 3 steps necessary for cervical cancer development
1. HPV infection
2. Progression to cervical intraepithelial neoplasia (CIN)
3. Invasion
HPV infection
must persist for
more than one year
Normal
Cervix
HPV Infection
HPV Clearance
Infected
Cervix
Progression
Invasion
CIN
Regression
Cancer
HOW DOES HPV CAUSE CERVICAL
CANCER?
HPV
E7
E6
Two of the proteins made by the human
papillomavirus are strongly associated
with the development of cervical cancer
E6 inhibits the
function of p53
E7 inhibits the
function of Rb
p53
Rb
p53 is a protein that controls
response to cellular stress
including DNA damage and viral
infection.
Rb is a protein that can prevent
cell division by blocking the
activity of transcription factors
NORMAL – CANCER CERVIX
• CIN I
<!% progress to
Cancer.
• CIN II
30% progress
to CIN III.
• CIN III
40% progress to
invasive cancer
after long term
HPV infection
NORMAL CERVIX
Low-Grade Dysplasia
(CIN1)
High-Grade Dysplasia
(CIN 2 or 3)
Cervical Cancer
CIN - LOSS OF STRATIFICATION, MATURATION & DIFFERENTIATION,
ALTERED C/N RATIO, PLEOMORPHIC CELLS, ALTERED STAINING,
HYPERCHROMATIC NUCLEI, ABNORMAL NUMBER CHROMOSOMES, ACTIVE
MITOSIS.
33-33-33
50-50
70-30
DIAGNOSIS OF CIN
• Symptomless, excessive discharge, postcoital bleeding.
• Pap’s smear - >21yrs or sexually active
and 3 yearly thereafter.
• HPV test – for >30 yrs, after Pap’s.
• Colposcopy - if Pap’s or HPV test positive, look for acetowhite areas,
mosaic, punctation or abnormal vessels.
PAP’S SMEAR
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Adequate smear contains cells from entire transformation zone –
squamous + endocervical cells.
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Conventional technique – Ayres spatula
Liquid Based Cytology ‘LBC’ – Thin Prep
Automated Pap’s
False negative 1%, false positive 5%
brush
PAPS SMEAR
Normal squamous cells
Dysplastic cells
Sensitivity – True Positive
Specificity – True Negative
Correlation of CERVICAL CYTOLOGY
Pap’s
WHO
CIN - Richart Betheseda
Normal
Negative
Negative
Normal limit
Negative
Infection/
Reparative
ASCUS/AGUS
LSIL
Inflammatory Atypical
Dysplasia
HPV atypia
Mild dysplasia CIN I
Mod.
dysplasia
Suggestive
malignancy
Malignant
CIN II
Severe
CIN III
dysplasia/CIS
Invasive ca.
Invasive ca.
HSIL
HSIL
Invasive ca.
HPV DNA TEST
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A sample of cells is taken from the cervix during a pelvic
examination, using a brush or spatula. The sample is
placed into a preservative and sent to a lab for testing.
The lab tests the sample for the presence of HPV DNA.
A positive test indicates HPV infection, but a positive
result does not indicate CIN or cervical cancer. Follow up
procedures (pap test and colposcopy) are
recommended.
The test detects
HPV DNA
If an HPV infection is present in the cervix,
HPV DNA will be detectable
HPV TESTS
• Digene HPV DNA Hybrid Capture 2 test. It tests for 13 high risk
and 5 low risk types of HPV*.
• HPV genotyping
• HPV Oncotect: HPV E6, E7 mRNA assay– identifies presence of
HPV E6, E7 mRNA (viral gene expression) in intact epithelial
cells.**
• OncoE6TM cervical test – Arbor Vita.
COLPOSCOPE
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Introduced by Hans Hinselmann in 1925.
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Study of surface epithelium of cervix and underlying tissue
stroma along with its vascular network.
Optical method for visualizing lower
female
genital tract under bright illumination and magnification.
INDICATIONS
• Evaluation of women with abnormal Pap’s smear, positive VIA or VILI, to
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localize or select punch biopsy site.
Evaluation of women with normal smear but suspicious cervix, post coital
bleeding or leucoplakia.
Persistent vaginal discharge.
Subclinical HPV infection.
Conservative Rx of CIN
Follow up after Rx of CIN III or invasive cancer.
COLPOSCOPE
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Low power, stereoscopic, binocular, field
microscope with powerful light source.
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Magnification 6x-40x.
Other instrumentsBivalve speculum, sponge forceps,
endocervical speculum & curette, punch
biopsy forceps.
SALINE TECHNIQUE
• Vascular pattern of cervix.
• Advisable to use a green filter to see vessels clearly.
Normal cervix
CIN III
Invasive cancer VIA
ACETIC ACID TEST
• 3-5% acetic acid, coagulates & clears cervical mucus.
• Causes reversible coagulation & precipitation of nuclear proteins &
cytokeratins.
ACETIC ACID TEST
• Normal squamous epithelium, little coagulation occurs as superficial epithelium
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is sparsely nucleated.
Areas of CIN undergo maximal coagulation due to high content of nuclear
protein & prevent light from passing through epithelium. Therefore
subepithelial vessel pattern is obliterated & epithelium appears “acetowhite”.
VIA
• Areas of high grade CIN & invasive
cancer turn densely white, thick opaque on
applying acetic acid, with well
demarcated margins.
• Low grade CIN, the whiteness is delayed
& less intense.
• Other acetowhite areas – immature
Cancer cervix
squamous epithelium, congenital
transformation zone, healing &
regenerating epithelium, leucoplakia,
condyloma.
VIA PROCEDURE
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Ask the woman is to lie down in a modified lithotomy position with leg rests or stirrups.
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Introduce a sterile vaginal speculum and open blades of the speculum to view the cervix.
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Proceed to identify the transformation zone, the upper limit of which is formed by the SCJ.
Observe the external genitalia and perineal region for any signs of excoriations, edema, vesicles, papules,
sores, ulceration and warts. Look for any swelling in the inguinal/femoral region.
Look for any vaginal discharge & observe the size and shape of the cervix.
Identify the external os, columnar epithelium (red in colour), squamous epithelium (pink) and the
squamocolumnar junction.
Look for ectropion, cervical polyp, nabothian cysts, healed laceration of the cervical lips, leukoplakia,
condylomata and signs of cervicitis. In postmenopausal women, the cervix appears pale and brittle, due to
thinning and atrophy of the squamous epithelium.
INTERPRETATION
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Discharge: Assess the characteristics of discharge in terms of quantity, colour, odour and thickness.
Thread-like, thin mucinous discharge from the external os indicates ovulation.
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Menstrual Bleeding: If heavy blood flow through the external os is observed in women during
menstruation, subject to VIA after 5-15 days.
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Ectropion the cervix has a large area of red appearance around the external os and the
squamocolumnar junction far away from the os. Extensive erosive red areas may be present on the
cervix, extending to the vagina in instances of severe cervical infection and inflammation.
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Nabothian cysts appear as bulging blue-white or yellow-white nodules, having a smooth delicate lining
with branching blood vessels.
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Leukoplakia appears as a smooth-surfaced, white area on the cervix before doing VIA that cannot be
removed or scraped off.
INTERPRETATION
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Observe whether there is any bleeding from the cervix, especially on touch, or ulcer or proliferative
growth. More advanced invasive cancers may present as a large exophytic growth with an
ulceroproliferative, bulging mass with polypoid or papillary excrescences, arising from the cervix or as a
predominantly ulcerating growth replacing most of the cervix.
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If no evidence of invasive cancer: Gently, but firmly, apply 5% acetic acid using a cotton swab
soaked in acetic acid. Wait for at least 1 minute before reading. The secretions should be gently wiped
off.
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A significant white lesion is defined as a lesion that appears white, thick and with well-defined margins
close to or at the SCJ. The results one minute after application of acetic acid should be reported.
Note how rapidly the acetowhite lesion appears and then disappears.
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Carefully observe:
• The intensity of the white colour of the acetowhite lesion: whether it is shiny white, cloudy-white,
pale-white or dull-white.
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The borders and demarcations of the white lesion: distinctly clear and sharp or indistinct diffuse
margins; raised or flat margins; regular or irregular margins.
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Whether the lesions are uniformly white in colour, or the colour intensity varies across the lesion, or
if there are areas of erosion within the lesion.
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Location of the lesion: is it in, near or far away from the transformation zone? Is it abutting
(touching) the squamocolumnar junction? Does it extend into the endocervical canal? Does it occupy
the entire or part of the transformation zone? Does it involve the entire cervix (which usually
indicates early preclinical invasive cancer)?
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Size (extent or dimensions) and number of the lesions.
VIA NEGATIVE
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No acetowhite lesions are observed on the
cervix .
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Nabothian cysts appear as button-like areas,
as whitish acne or pimples.
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Dot-like areas are present in the endocervix,
which are due to grapelike columnar
epithelium staining with acetic acid.
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Angular, irregular, digitating acetowhite
lesions, resembling geographical regions,
distant (detached) from the squamocolumnar
junction (satellite lesions).
VIA POSITIVE
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There are distinct, well-defined, dense (opaque, dull or
oyster-white) acetowhite areas with regular or irregular
margins, close to or abutting the sjc in the transformation
zone or close to the external os if the scj is not visible.
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The entire cervix becomes densely white after the
application of acetic acid.
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Condyloma and leukoplakia occur close to the scj, turning
intensely white after application of acetic acid. (Condyloma
is not VIA positive. By definition VIA positives are gross
manifestations of CINs. While they can be treated by cryo,
calling them VIA positive will skew the numbers of VIA
positive as these are relatively more common – genital
warts).
VIA POSITIVE: INVASIVE CANCER
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There is a dull, opaque, dense
acetowhite area, with raised and
rolled-out margins, irregular surface
and bleeding on touch in the posterior
lip. The lesion is extending into the
cervical canal. The bleeding obliterates
acetowhitening.
SCHILLERS LUGOL IODINE TEST
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Original & mature squamous metaplastic
epithelium is glycogenated, but CIN & invasive
cancer contain little/no glycogen.
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Normal glycogen containing squamous epithelium
stains mahogany brown .
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Tissues that do not stain- Columnar epithelium,
immature squamous epithelium, erosion, CIN,
invasive cancer, leucoplakia, Condyloma.
VILI: TEST-NEGATIVE
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The squamous epithelium turns brown
and columnar epithelium does not
change color.
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There are scattered and irregular,
partial or non-iodine uptake areas
associated with immature squamous
metaplasia or inflammation (leopard
skin).
Photo source: IARC
VILI: TEST-POSITIVE
• Well-defined, bright yellow iodine
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non-uptake areas touching the
squamocolumnar junction (SCJ).
Well-defined, bright yellow iodine
non-uptake areas close to the os if
SCJ is not seen, or covering the
entire cervix.
Photo source: IARC
VILI: SUSPICIOUS FOR CANCER
• Clinically visible ulcerative,
cauliflower-like growth or ulcer;
oozing and/or bleeding on touch.
Photo source: IARC
Accuracy of screening tests in developing countries:
range in sensitivity and specificity
Test
Sensitivity
Specificity
Cytology
31-78%
91-99%
HPV testing
61-90%
62-94%
VIA
50-96%
44-97%
VILI
44-93%
75-85%
MANAGEMENT
• Mild dysplasia
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Observation
Treat infection, trichomoniasis
Menopausal, give hormones
Repeat Pap’s 3 monthly, till 3 negative smear
• Moderate dysplasia/ CIN III
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Colposcpic directed biopsy
Cone biopsy, cold knife/ laser conization
LEEP/LLETZ, cryocautery, CO2 laser
Hysterectomy
Loop electrosurgical excision procedure – large loop excision of transformation zone
SEE & TREAT
Cytology, Colposcopy, VIA, LLETZ
• No evidence of malignancy on cytology or colposcopy
• No endocervical involvement, ECC –ve
• Whole of transformation zone visualised
• No disparity between cytology & HPE
• Patient amenable to follow up.
CRYOCAUTERY
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Apply acetic acid to outline the abnormality and begin cryotherapy. There are 2 techniques for
freezing the cervical lesion. The double freeze of 3 minute freeze + 5 minute rest + 3 minute
freeze or the single freeze of 5 min straight.
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Tell the woman she might feel some discomfort or cramping while freezing.
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Ensure that the vaginal wall is not in contact with the cryoprobe or which may cause a freezing
injury to the vagina.
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Set the timer and release the gas trigger to cool the probe.
Wipe the cryoprobe surface with saline to ensure optimum effectiveness.
Apply the cryoprobe tip in the centre of the os and make sure the probe adequately covers the
lesion. If the lesion extends more than 2mm beyond the probe, discontinue the Procedure. Explain
to the woman what needs to be done for her as an alternative.
• Ice formation on the tip of the cryoprobe is observed and on the cervix. When the frozen
area extends 4–5 mm beyond the edge of the cryoprobe, freezing is adequate.
• Allow two cycles of freezing and thawing: 3 minutes freezing + 5 minutes thawing + 3
minutes freezing.
• Once the second freezing is complete, allow time for thawing before attempting to remove
the probe from the cervix. Removing it before it is fully thawed will pull tissue off the cervix.
• Gently rotate the probe on the cervix to remove it. The area you have frozen will appear
white.
• Examine the cervix for bleeding. If bleeding is noted, apply Monsel’s paste.
• Do not pack the vagina.
• Remove the speculum
POST PROCEDURE
• Instruct the woman to abstain from intercourse and not to use vaginal tampons for 4 weeks, until the discharge
stops completely. This to avoid infection. She should use clean pads
• Provide condoms for use if she cannot abstain from intercourse as instructed. Teach her how to use them. This
may usually be allowed from the 3rd week.
• Invite her to return in 2–6 weeks to be checked for healing, and again in 12 months for a repeat VIA or
colposcopy.
• Inform her of possible complications and ask her to return immediately if she notes:
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fever with temperature higher than 38 °C or shaking chills;
severe lower abdominal pain;
foul-smelling or pus-like discharge;
bleeding for more than two days or bleeding with clots.
Perform a pelvic examination to check for healing 2–6 weeks after the cryotherapy.
• At 12 months do a repeat VIA or colposcopy and take a biopsy if necessary.
LOOP ELECTRICAL EXCISION PROCEDURE
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Colposcopic assessment should be carried out immediately before LEEP to confirm that the location
and linear extent of the lesion are amenable to effective LEEP.
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The application of Lugol’s iodine solution is helpful to outline lesion margins before the start of
treatment.
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An insulated vaginal speculum with an electrically insulating coating or a speculum covered with a
latex condom should be used.
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Avoid causing pain by inadvertently touching the vaginal walls with the activated electrode. The
later possibility may be avoided by using an insulated vaginal sidewall retractor in addition to an
insulated vaginal speculum or by using a speculum covered by a condom
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A smoke evacuation system with a high rate of flow and a means of filtering out the smoke
particles and odour is mandatory.
PROCEDURE
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Local anesthesia is achieved 30 seconds after injection of a total of 5ml or less of 1% xylocaine into
the stromal tissue of the ectocervix. The injections are given in a ring pattern 1-2 mm deep (at 3, 6, 9
and 12 o’clock) at the periphery of the lesion and transformation zone.
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A vasoconstrictor agent such as vasopressin may be added to LA.
Use least amount of power that will effectively perform the electro surgery, so as to minimize the risk to
the patient’s normal tissues and ensure that the excised specimen is inacceptable condition for
pathological assessment. Use blend mode for cutting and coagulation mode for hemostasis. The
commonly used power settings for the different loop electrodes are as follows:
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1.0 x 1.0 cm: 30 watts;
1.5 x 0.5 cm: 35 watts;
2.0 x 0. 8 cm: 40 watts;
2.0 x 1.2 cm: 50 watts.
3 mm and 5 mm ball electrodes: 30 watts and 50 watts, coagulation mode.
When possible, remove lesion with one pass of the loop electrode using a loop that is wider than the
lesion(s) and the transformation zone to be removed. The depth of the loop should be at least 5 mm.
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Introduce loop into the tissue 5mm outside the outer boundary of the lesion. It is important not to push the electrode in,
but to let it cut its own way. Direct the loop gradually into the cervix until the cross bar nearly comes in contact with
the epithelial surface. Then the loop is guided along parallel to the surface (horizontally or vertically, depending on
the orientation of the direction of cutting until the point is reached just outside the opposite border of the lesion.
Withdraw the loop is then slowly, still keeping it at right angles to the surface. The current is switched off as soon as
the loop exits the tissue.
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The setting on the electrosurgical generator is changed to fulguration and the appropriate power is selected. The
surface of the excisional crater is fulgurated using 3 or 5 mm ball electrode. The edges of the crater should also be
fulgurated to preserve the squamocolumnar junction in the visible ectocervix.
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If active bleeding occurs and is difficult to control using the ball electrode, use macroneedle style electrode to apply
the fulguration current in a much more concentrated and localized fashion to a bleeding site.
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If satisfactory hemostasis has been obtained, coat the surface of the crater with Monsel’s paste and remove the
speculum.
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If a lesion involves the endocervical canal and is not likely to be removed with the depth of the usual single-layer
pass ( this type of excision can reach a maximum of 1.6 cm into the endocervical canal). Or if the distal or upper
extent of the lesion in the canal cannot be seen and if the distal end of the lesion extends more than 1 cm into the
canal, such patients should undergo cold-knife conization.
FOLLOW UP
• Give instructions on self-care and what symptoms to expect after treatment. Women should be advised that
they will have a brown or black discharge lasting between a few days and two weeks.
• To promptly report back if the discharge persists for more than two weeks, if discharge becomes malodorous
and/or is associated with lower abdominal pain or if profuse bleeding develops.
• The risk of post-operative infection can be reduced by treating adequately the woman with a likely diagnosis
of PID, cervicitis, vaginal trichomoniasis or bacterial vaginosis before performing LEEP. If a woman presents
post-operatively with a malodorous discharge, it should be cultured if possible and empirical treatment
prescribed with antibiotics for PID (doxycycline 100 mg BD x7 days and metronidazole 400 mg orally TDS
X7days).
• If post-operative pain occurs, use acetaminophen or ibuprofen.
• Not to use a vaginal douche or tampons, or to have sexual intercourse for one month.
• A follow-up appointment should be made for review at 9-12 months after treatment.
OSMANABAD RCT OF CERVICAL SCREENING, INDIA
Study
RESULTS OF TREATMENT OF CIN
Treatment
Total number
Cured (%)
Cryotherapy
562
477 (85%)
LEEP
422
357 (85%)
HPV VACCINE
Gardasil ®
What is it?
Gardasil ® is a vaccine approved by the Food and Drug Administration (FDA) to
protect against four types of HPV: 6, 11, 16, and 18
Who can get it?
 The CDC and FDA recommends girls and women aged 9-26 should get the
vaccine.
Why 6, 11, 16, and 18?
 Types 6 and 11 cause most cases of genital warts
 Types 16 and 18 are high-risk types that can cause cervical cancer (~70%)
How effective is it?
 Studies have shown the vaccine to be almost 100% effective in preventing
diseases caused by the 4 types of HPV it covers

OF GREAT IMPORTANCE…
Cervarix™
What is it?
 Cervarix™ is an HPV vaccine produced by GlaxoSmithKline that has not yet
been approved by the Food and Drug Administration (FDA). It has been
approved in Australia and Europe.
What does it protect against?
 Cervarix™ protects against types 16 and 18. These are high-risk types that
cause cervical cancer over 70% of all cervical cancer cases.
DOWN STAGING OF CERVICAL CANCER
WHO
• In resource poor settings
• Aims to pick up cervical cancer in early stage when amenable to treatment
• Health workers trained to do per speculum examination of cervix and refer
bad cervices for cytology/ biopsy
• Low sensitivity & specificity
• Can be helped by VIA / VILI
MANAGEMENT OF CERVICAL
CANCER
INVASIVE CANCER CERVIX
ETIOLOGY
• Age, 2 peaks – 35yrs, 50-55yrs
• Genetic & racial factors, rare in Jews & Muslims, high in Africans.
• Low SE status, lack of hygiene
• Early age at coitus, frequent intercourse & change of partners, 1st wife had
•
•
•
cervical cancer, parous women
HPV 16, 18, 31, 45
OCPs favour CIN
Smokers
PATHOGENESIS

There are 3 steps necessary for cervical cancer development
1. HPV infection
2. Progression to cervical intraepithelial neoplasia (CIN)
3. Invasion
HPV infection
must persist for
more than one year
Normal
Cervix
HPV Infection
HPV Clearance
Infected
Cervix
Progression
Invasion
CIN
Regression
Cancer
HOW DOES HPV CAUSE CERVICAL CANCER?
HPV
E7
E6
Two of the proteins made by the human
papillomavirus are strongly associated
with the development of cervical cancer
E6 inhibits the
function of p53
E7 inhibits the
function of Rb
p53
Rb
p53 is a protein that controls
response to cellular stress
including DNA damage and viral
infection.
Rb is a protein that can prevent
cell division by blocking the
activity of transcription factors
SQUAMOCOLUMNAR JUNCTION
Ectropion prominent in puberty, pregnancy, OCP
Everted columnar epithelium is exposed to high vaginal acidity, leading to destruction of
cells.
Proliferation of subcolumnar reserve cells.
Reserve cell hyperplasia.
Immature metastatic squamous epithelium.
Normal glycogen containing
mature squamous epithelium.
Infection with HPV 16, 18
Atypical or dysplastic squamous
epithelium.
CLASSIFICATION OF HISTOLOGICAL FINDINGS:
CERVICAL INTRAEPITHELIAL NEOPLASIA
•
Cervical intraepithelial neoplasia (CIN)1
•
•
•
CIN 1: Mild dysplasia; includes condyloma (anogenital warts)
CIN 2: Moderate dysplasia
CIN 3: Severe dysplasia; includes CIS
CIN1
Normal
CIN 1
(condylom
a)
CIN 1
(mild
dysplasia)
CIN 2
(moderate
dysplasia)
CIN 3
(severe dysplasia/CIS)
Invasive
Cancer
Histology of
squamous
cervical
epithelium1
Basal cell
Basal membrane
CIN caused by HPV can clear without treatment.2
1. Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press; 2002:569–612.
2. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192.
CERVICAL CANCER RISK FACTORS
• Risk factors for persistent HPV
infection
• Lifetime number of sexual partners
• Age at first intercourse
• Smoking
• Oral contraceptive use
• Male partner sexual behavior
• Additional risk factors
•
•
•
•
•
Age
Genetics
Low socioeconomic class
Nutrition
Immune suppression
HISTOPATHOLOGICAL TYPES
• Squamous cell carcinoma – 80-90%
• Large cell keratinizing – 20%
• Large cell non-keratinizing – 60%
• Small cell non-keratinizing – 20%
• Verrucous
• Adenocarcinoma – 5 -10%
• Endometriod adenocarcinoma
• Clear cell adenocarcinoma
• Adenosquamous carcinoma
• Small cell carcinoma
• Undifferentiated carcinoma
•
•
•
•
Grade I well differentiated,
Grade II moderately
differentiated,
Grade III poorly differentiated.
ADENOCARCINOMA CERVIX
• Younger women, smokers or pill users
• Arises in endocervix
• Ulcerative, infilterative, hard indurated barrel shaped cervix
• Anaplasia common
SQUAMOUS CELL CANCER
• Starts in squamocolumnar junction
• Hypertrophic or exophytic
• Eroding or ulcerative
• Infilterative
SQUAMOUS CELL CANCER
WELL DIFFERENTIATED
SPREAD
• Direct extension to body of uterus, vagina,
bladder & cellular tissues of broad
ligament, & uterosacral ligament.
• Blood stream to ovaries, brain, bones, lung.
• Lymphatic from lymphatics in base of broad
& uterosacral ligament to Obturator, Sacral,
External & Internal Iliac Lymph nodes.
SYMPTOMS & SIGNS
•
•
•
•
•
•
Symptomless
Postcoital bleeding
Irregular uterine bleeding or discharge
Late frequency, dysuria, incontinence
Rectal pain, backache sciatica, leg
edema
Loss of weight, anorexia, malaise
•
•
•
•
•
Hard, indurated
Irregular
Bleeds on touch
Friable
Fixity
DIAGNOSIS & CLINICAL STAGING
•
•
•
•
•
Per speculum, bimanual & per rectal examination
Colposcopy, directed biopsy, endocervical curettage
Hysteroscopy, cystoscopy, proctoscopy
Intravenous pyelography
X-Ray Chest & skeleton.
Optional – laparoscopy, ultrasonography, CT scan,
MRI scan, PET scan.
FIGO STAGING
•
Stage 0 carcinoma in situ
•
Stage 1 Cervical carcinoma confined to uterus. Spread to corpus disregarded.
•
Stage 1A invasive cancer diagnosed only on microscopy
•
Stage 1A1 stromal invasion <3mm depth & <7mm horizontal spread.
•
Stage 1A2 stromal invasion >3mm but <5mm in depth, horizontal spread <7mm.
STAGE 1B OVERT CANCER CONFINED TO
CERVIX
• Stage 1B1 clinically
visible lesion 4cm or less in
greatest dimension.
• Stage 1B2 clinically
visible lesion >4cm in
greatest dimension.
• Stage 2 Tumor invades beyond the uterus but not to the pelvic wall, or to the
•
•
lower third of vagina.
Stage 2A without parametrial involvement
Stage 2B with parametrial involvement.
• Stage 3 tumor extends to lateral pelvic wall, and/or involves lower third of
•
•
vagina and/or causes hydronephrosis, nonfunctioning kidney.
Stage 3A tumor extends to lower third vagina, no extension to pelvic wall.
Stage 3B tumor extends to pelvic wall.
STAGE III A
• Stage 4A tumor invades
mucosa of bladder
rectum and/or extends
beyond true pelvis.
• Stage B distant
metastasis.
PROGNOSIS
•
•
•
•
•
•
•
•
•
Extent of growth at time of treatment
Site - endocervical more dangerous
Size – hypertrophic, florid, massive growth filling vagina
Histology - adenocarcinoma
Age – young person
Ureteric obstruction
Grade - poorly differentiated or anaplastic
Lymph node involvement
Metastasis
TREATMENT PATTERNS IN CARCINOMA CERVIX
Sx (5%)
Comb (12%)
RT (83%)
TATA HOSPITAL CANCER REGISTRY 2000
MANAGEMENT
• Stage 1A1
• Conisation
• Extrafascial total
abdominal hysterectomy
(type1 Radical)
• Stage 1A2
• Type 2 Radical Werthiem’s
hysterectomy
• Pelvic node dissection
Stage 1B + 2A
• Type III radical
hysterectomy with pelvic
lymph node sampling.
Meigs hysterectomy
Schauta Amreich opt.
Mitra’s hysterectomy
with bilateral
extraperitoneal
lymphadenectomy
Stage 1B exophytic
Indications of surgery
• Stage1 & 2A
• Young patient
• Preserve ovarian
function, ovaries involved
in <1%
• Pregnancy
• Chronic PID, fibroids
• Endocervical barrel
shape, columnar
adenocarcinoma.
Stage 1B
Complications
• Mortality 1-2%
• Hemorrhage, shock, peritonitis,
paralytic ileus, intestinal
obstruction, thromboembolism
• Bladder atony, cystitis, pyelitis,
hydronephrosis,stenosis of
ureter.
Stage 1B endocervical
Chemotherapy
• Cisplatinium based
• Neoadjuvant chemotherapy, for
preopt. large bulky tumors
• Concurrent chemotherapy with RT
for bulky advanced cancer.
Stage 2A
B
Stage 2B, 3 & 4
Radiotherapy
• EBRT+ ICRT
• Primary target, Point A EBRT
50Gy/5-6weeks (Linear
accelerator Cobalt60) + LDR
ICRT 30-35GY (LDR or HDR)
• Secondary target, Point B
EBRT 50Gy/5weeks
A
Stage 2B
1 Gray == 100rads
Radiotherapy +
Concurrent chemotherapy
Cis platinium 40mg/m2 weekly
during external radiation.
Stage 3A
Interstial brachytherapy
• Transperineal perforated
templates with iridium-192
or iodine125
• Advanced parametrial
disease
• Distorted anatomy
• Postopt. or postradiation
recurrence
Stage 3B
Complications
• Flare up PID
• Diarrhoea, abdominal
cramps, nausea, bowel bleed
• Arteritis, fibrosis,
• Radiation proctitis
• Subacute intestinal
obstruction
• Fistula
• Avascular necrosis femur neck
• Menopausal symptoms
Stage 4A
5 YEAR SURVIVAL RATES
• Overall
• Radiotherapy
Stage 1- 85%
Stage 1 - 80-90%
Stage 1B
Stage 2 - 55-70%
87-91% - node -ve
Stage 3 - 30-35%
51-67% - node +ve
Stage 4 - 10%
Stage 2 - 60%
• Surgery
Stage 3 - 33%
Stage 1 - 70%
Stage 4 – 10%
Stage 2 - 45-50%