Screening for cervical cancer - PowerPoint Presentation

Slide1

Screening for cervical cancer

The Obstetrics & Gynecological Society of Bhopal

&

AMPOGS Research Public Welfare SocietySlide2

BREAST

AND GENITAL TRACT CANCER INCIDENCE RATES PER 100,000

FEMALES worldwide

31.3

17.4

8.3

3.2

21.2

20.1

19.3

24.6

28.2

27.5

23.3

23.2

16.6

19.3

20.2

15.7

7.6

7.2

6.5

7.2

7.2

4.8

1.3

1.4

1.6

2.3

2.5

2.4

0

5

10

15

20

25

30

35

1970

1975

1980

1985

1990

1995

2000

YEAR

RATE

BREAST

CERVIX UTERI

OVARY

CORPUS UTERISlide3

Breast & genital tract cancer IndiaSlide4

Cervical cancer Incidence

Cervical

cancer

is the fourth common cancer in women worldwide. >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

.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.Slide5

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

PregnancyLess than 6 weeks of deliveryHad hysterectomy doneScreening to be done every 5 yearsSlide6

Uterine Cervix

Lower fibromuscular portion of 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.

ENDOMETRIUM

MYOMETRIUM

INTERNAL OS

CERVICAL CANAL

EXTERNAL OS

VAGINA

PORTIO VAINALIS

SUPRAVAGINAL

CERVIXSlide7

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.Slide8

Ectocervix

Covered by stratified,

nonkeratinising

, glycogen containing squamous epithelium.Opaque, pale pink in colour.Overall, from basal to superficial layers, cells undergo an increase in size and reduction in nuclear size.Slide9

Ectocervix

Intermediate and superficial cells contain 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 colposcopySlide10

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.

cellsSlide11

Endocervix

Columnar epithelium is thrown into multiple longitudinal folds protruding into lumen of canal.

It forms invaginations into substance of cervical canal forming

endocervical crypts.Gives grainy appearance on visual inspection.Slide12

Endocervix

Glycogen and mitosis are absent in columnar epithelium.

Terminal vessels of columnar epithelium consists of inter

twining capillaries, forming a multi channel network.Slide13

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. Slide14

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 CELLSSlide15

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.Slide16

Squamocolumnar Junction

Immature metastatic squamous epithelium.

Normal glycogen containing mature squamous epithelium.

Immature squamous epitheliumSlide17

Squamocolumnar Junction

Immature metastatic squamous epithelium

Infection with oncogenic virus HPV types.

Atypical or dysplastic squamous epithelium.

ImmatureMetastatic Squamous epithelium

Mature

Metastatic

Squamousepithelium

Original

Squamous Epithelium.Slide18

Transformation Zone

Region of the cervix where columnar epithelium has been replaced and/or is being replaced by new metastatic squamous epithelium.

Its the area of cervix, bound by original SCJ at distally & metastatic SCJ proximally.

In premenopausal women the TZ is fully located on ectocervix.After menopause cervix shrinks & TZ may move partially or fully into

cervical canal.Slide19

Transformation Zone

Normal TZ is composed of immature &/or 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

cryptSlide20

Harald

zur

HausenSlide21

Human Papillomavirus (HPV)

Double stranded circular DNA molecule.

Long known to cause warts

Found in many cancers tooOver 100 types identifiedMost benign, but 15-20 can cause cancersVery common20,000,000 current cases in US

6,200,000 new cases annually80% of women have HPV by age 5050% of college students are infectedSlide22

HPV & Cervical Cancer

HPV

recognized as the underlying cause of

cervical cancer since 1996NIH Consensus Conference on Cervical Cancer, 1996World Health Organization/European Research Organization on Genital Infection and Neoplasia, 1996Slide23

Common HPV Types and their effects

HPV Types

Lead to:

Low-Risk

High-Risk

HPV 6, 11,

40

, 42, 43, 44, 54, 61, 70, 72, 81

HPV 16, 18,31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82

Benign cervical changes

Genital warts

Precancer cervical changesCervical cancerAnal and other cancers

1. Cox. Baillière’s Clin Obstet Gynaecol. 1995;9:1.

2. Munoz et al. N Engl J Med. 2003;348:518. Slide24

Human Papillomavirus

Cancer of cervix 100%

Cancer of

esophagus . Cancer of skin .

Cancer of X,Y,Z…. .

Cancer of mouth 3%

Cancer of throat 12%

Cancer of penis 40%

Cancer of vulva, vagina 40%

Cancer of anus 90%

Parkin DM et al.

CA Cancer J Clin

2005; 55:74-108.Slide25

PATHOGENESIS

There are 3 steps necessary for cervical cancer development

HPV infection

Progression to cervical intraepithelial neoplasia (CIN)

Invasion CIN

Infected

Cervix

HPV Infection

HPV Clearance

Normal

Cervix

Cancer

Progression

Regression

HPV infection

must persist for

more than one year

InvasionSlide26

How Does HPV Cause Cervical Cancer?

p53

E6

E7

Rb

X

X

HPV

E6 inhibits the function of p53

E7 inhibits the function of

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

Two of the proteins made by the human papillomavirus are strongly associated with the development of cervical cancerSlide27

Normal – Cancer cervix

CIN I

<!% progress to

Cancer.CIN II30% progressto CIN III.CIN III40% progress to

invasive cancerafter long term HPV infectionSlide28

Normal Cervix

Low-Grade Dysplasia

(CIN1)

Cervical Cancer

High-Grade Dysplasia

(CIN 2 or 3)

Slide29

CIN - loss of stratification, maturation & differentiation, altered C/N ratio,

pleomorphic

cells, altered staining, hyperchromatic

nuclei, abnormal number chromosomes, active mitosis. 33-33-33

50-5070-30Slide30

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. Slide31

Pap’s smear

Adequate smear contains cells from entire transformation zone –

squamous

+ endocervical cells.Conventional technique – Ayres spatulaLiquid Based Cytology ‘LBC’ – Thin PrepAutomated Pap’sFalse negative 1%, false positive 5%

brushSlide32

Paps smear

Normal squamous cells

Dysplastic cells

Sensitivity – True Positive

Specificity – True NegativeSlide33

Pap’s

WHO

CIN - Richart

Betheseda

Normal

Negative

Negative

Normal limit

Inflammatory

Atypical

Negative

HPV atypia

Infection/

Reparative

ASCUS/AGUS

Dysplasia

Mild dysplasia

CIN I

LSIL

Mod. dysplasia

CIN II

HSIL

Suggestive malignancy

Severe dysplasia/CIS

CIN III

HSIL

Malignant

Invasive ca.

Invasive ca.

Invasive ca.

Correlation of CERVICAL CYTOLOGYSlide34

HPV DNA Test

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.

If an HPV infection is present in the cervix,

HPV DNA will be detectable

The test detects

HPV DNASlide35

HPV tests

Digene

HPV DNA Hybrid Capture 2 test. It tests for 13 high risk and 5 low risk types of HPV*.

HPV genotypingHPV 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.Slide36

Colposcope

Introduced by Hans

Hinselmann in 1925.

Optical method for visualizing lower female genital tract under bright illumination and magnification.Study of surface epithelium of cervix and underlying tissue stroma along with its vascular network.Slide37

Indications

Evaluation of women with abnormal Pap’s smear, positive VIA or VILI, to 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.Slide38

Colposcope

Low power, stereoscopic, binocular, field microscope with powerful light source.

Magnification 6x-40x.

Other instruments- Bivalve speculum, sponge forceps, endocervical speculum & curette, punch biopsy forceps.Slide39

Saline Technique

Vascular pattern of cervix.

Advisable to use a green filter to see vessels clearly.

Normal cervix

CIN III

Invasive cancer VIASlide40

Acetic Acid Test

3-5% acetic acid, coagulates & clears cervical mucus.

Causes reversible coagulation & precipitation of nuclear proteins & cytokeratins.Slide41

Acetic Acid Test

Normal squamous epithelium, little coagulation occurs as superficial epithelium 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”. Slide42

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 squamous epithelium, congenital transformation zone, healing & regenerating epithelium, leucoplakia, condyloma.

Cancer cervixSlide43

VIA procedure

Ask the woman is to lie down in a modified lithotomy

position

with leg rests or stirrups. 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.Introduce a sterile vaginal speculum and open blades of the speculum to view the cervix.

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.Proceed to identify the transformation zone, the upper limit of which is formed by the SCJ. 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. Slide44

interpretation

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. Menstrual Bleeding: If heavy blood flow through the external os is observed in women during menstruation, subject to VIA after 5-15 days. 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.Nabothian cysts appear as bulging blue-white or yellow-white nodules, having a smooth delicate lining with branching blood vessels. Leukoplakia appears as a smooth-surfaced, white area on the cervix before doing VIA that cannot be removed or scraped off.Slide45

interpretation

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. 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. 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.Slide46

Carefully observe:

The intensity

of the white colour of the

acetowhite lesion: whether it is shiny white, cloudy-white, pale-white or dull-white.The borders and demarcations of the white lesion: distinctly clear and sharp or indistinct diffuse margins; raised or flat margins; regular or irregular margins.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.

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)?Size (extent or dimensions) and number of the lesions. Slide47

VIA negative

No

acetowhite

lesions are observed on the cervix .Nabothian cysts appear as button-like areas, as whitish acne or pimples.Dot-like areas are present in the

endocervix, which are due to grapelike columnar epithelium staining with acetic acid.Angular, irregular, digitating acetowhite lesions, resembling geographical regions, distant (detached) from the squamocolumnar junction (satellite lesions).Slide48

VIA positive

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.The entire cervix becomes densely white after the application of acetic acid.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).Slide49

Via positive: invasive cancer

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.Slide50

Schillers Lugol Iodine Test

Original & mature squamous metaplastic epithelium is

glycogenated

, but CIN & invasive cancer contain little/no glycogen.Normal glycogen containing squamous epithelium stains mahogany brown .Tissues that do not stain- Columnar epithelium, immature squamous epithelium, erosion, CIN, invasive cancer, leucoplakia, Condyloma

. Slide51

VILI:

test-negative

The squamous epithelium turns brown and columnar epithelium does not change

color.There are scattered and irregular, partial or non-iodine uptake areas associated with immature squamous metaplasia or inflammation (leopard skin).

Photo source: IARCSlide52

VILI:

test-positive

Well-defined, bright yellow iodine 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: IARCSlide53

VILI:

Suspicious for cancer

Clinically visible ulcerative, cauliflower-like growth or ulcer; oozing and/or bleeding on touch.

Photo source: IARCSlide54

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%Slide55

Management

Mild dysplasia

Observation

Treat infection, trichomoniasisMenopausal, give hormonesRepeat Pap’s 3 monthly, till 3 negative smear Moderate dysplasia/ CIN IIIColposcpic directed biopsyCone biopsy, cold knife/ laser

conizationLEEP/LLETZ, cryocautery, CO2 laserHysterectomy Loop electrosurgical excision procedure – large loop excision of transformation zoneSlide56

See & treat

Cytology, Colposcopy, VIA, LLETZ

No evidence of malignancy on cytology or colposcopy

No endocervical involvement, ECC –veWhole of transformation zone visualisedNo disparity between cytology & HPEPatient amenable to follow up.Slide57

Cryocautery

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.Tell the woman she might feel some discomfort or cramping while freezing.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.Ensure that the vaginal wall is not in contact with the cryoprobe or which may cause a freezing injury to the vagina.Set the timer and release the gas trigger to cool the probe.Slide58

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 speculumSlide59

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 3

rd 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: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.Slide60

Loop electrical excision procedure

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.

The application of Lugol’s iodine solution is helpful to outline lesion margins before the start of treatment. An insulated vaginal speculum with an electrically insulating coating or a speculum covered with a latex condom should be used. 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

A smoke evacuation system with a high rate of flow and a means of filtering out the smoke particles and odour is mandatory. Slide61

procedure

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. 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: 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. Slide62

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.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. 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. If satisfactory hemostasis has been obtained, coat the surface of the crater with Monsel’s paste and remove the speculum

.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.Slide63

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.Slide64

RESULTS OF TREATMENT OF CIN

Treatment

Total number

Cured (%)

Cryotherapy

562

477 (85%)

LEEP

422

357 (85%)

O

SMANABAD

RCT

OF

C

ERVICAL

S

CREENING,

I

NDIA

StudySlide65

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 18Who 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 coversSlide66

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.Slide67

Down staging of cervical cancer

WHO

In resource poor settings

Aims to pick up cervical cancer in early stage when amenable to treatmentHealth workers trained to do per speculum examination of cervix and refer bad cervices for cytology/ biopsyLow sensitivity & specificityCan be helped by VIA / VILISlide68

Management of cervical cancerSlide69

Invasive Cancer CervixSlide70
Slide71

Etiology

Age, 2 peaks – 35yrs, 50-55yrs

Genetic & racial factors, rare in Jews & Muslims, high in Africans.

Low SE status, lack of hygieneEarly age at coitus, frequent intercourse & change of partners, 1st wife had cervical cancer, parous women HPV 16, 18, 31, 45OCPs favour CIN

Smokers Slide72

PATHOGENESIS

There are 3 steps necessary for cervical cancer development

HPV infection

Progression to cervical intraepithelial neoplasia (CIN)

Invasion CIN

Infected

Cervix

HPV Infection

HPV Clearance

Normal

Cervix

Cancer

Progression

Regression

HPV infection

must persist for

more than one year

InvasionSlide73

How Does HPV Cause Cervical Cancer?

p53

E6

E7

Rb

X

X

HPV

E6 inhibits the function of p53

E7 inhibits the function of

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

Two of the proteins made by the human papillomavirus are strongly associated with the development of cervical cancerSlide74

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.Slide75

Classification of Histological Findings:

Cervical Intraepithelial Neoplasia

Cervical intraepithelial neoplasia (CIN)

1CIN 1: Mild dysplasia; includes condyloma (anogenital warts)CIN 2: Moderate dysplasiaCIN 3: Severe dysplasia; includes CIS

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.

CIN

1

Normal

CIN 1

(

condyloma

)

CIN 1

(mild dysplasia)

CIN 2 (moderate dysplasia)

CIN 3

(severe dysplasia/CIS)

Invasive Cancer

Histology of

squamous

cervical epithelium

1

Basal cell

Basal membrane

CIN caused by HPV can clear without treatment.

2Slide76

Cervical Cancer Risk Factors

Risk factors for persistent HPV infection

Lifetime number of sexual partners

Age at first intercourseSmokingOral contraceptive useMale partner sexual behaviorAdditional risk factorsAgeGenetics

Low socioeconomic classNutritionImmune suppressionSlide77

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 adenocarcinomaClear cell adenocarcinomaAdenosquamous carcinomaSmall cell carcinomaUndifferentiated carcinoma

Grade I well differentiated,

Grade II moderately differentiated, Grade III poorly differentiated.Slide78

Adenocarcinoma

cervix

Younger women, smokers or pill users

Arises in endocervixUlcerative, infilterative, hard indurated barrel shaped cervixAnaplasia common Slide79

Squamous cell cancer

Starts in

squamocolumnar

junctionHypertrophic or exophyticEroding or ulcerativeInfilterative Slide80

Squamous cell cancer

well differentiatedSlide81

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.Slide82

Symptoms & Signs

Symptomless

Postcoital bleeding

Irregular uterine bleeding or dischargeLate frequency, dysuria, incontinenceRectal pain, backache sciatica, leg edemaLoss of weight, anorexia, malaise

Hard, induratedIrregularBleeds on touchFriableFixity Slide83

Diagnosis & Clinical Staging

Per speculum, bimanual & per rectal examination

Colposcopy, directed biopsy, endocervical curettage

Hysteroscopy, cystoscopy, proctoscopyIntravenous pyelographyX-Ray Chest & skeleton.Optional – laparoscopy, ultrasonography, CT scan, MRI scan, PET scan.Slide84

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 microscopyStage 1A1 stromal invasion <3mm depth & <7mm horizontal spread.Stage 1A2 stromal invasion >3mm but <5mm in depth, horizontal spread <7mm.Slide85

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.Slide86

Stage 2 Tumor invades beyond the uterus but not to the pelvic wall, or to the lower third of vagina.

Stage 2A without

parametrial

involvementStage 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.Slide87

Stage III aSlide88

Stage 4A tumor invades mucosa of bladder rectum and/or extends beyond true pelvis.

Stage B distant metastasis. Slide89

Prognosis

Extent of growth at time of treatment

Site -

endocervical more dangerousSize – hypertrophic, florid, massive growth filling vaginaHistology - adenocarcinoma Age – young person

Ureteric obstructionGrade - poorly differentiated or anaplasticLymph node involvementMetastasis Slide90

Sx (5%)

RT (83%)

Comb (12%)

TREATMENT PATTERNS IN CARCINOMA CERVIX

TATA HOSPITAL CANCER REGISTRY 2000Slide91

Management

Stage 1A1

Conisation

Extrafascial total abdominal hysterectomy(type1 Radical)Stage 1A2Type 2 Radical Werthiem’s hysterectomyPelvic node dissection Slide92

Stage 1B + 2A

Type III radical hysterectomy with pelvic lymph node sampling.

Meigs

hysterectomySchauta Amreich opt.Mitra’s hysterectomywith bilateral extraperitoneal

lymphadenectomy

Stage 1B exophyticSlide93

Indications of surgery

Stage1 & 2A

Young patient

Preserve ovarian function, ovaries involved in <1%PregnancyChronic PID, fibroidsEndocervical barrel shape, columnar adenocarcinoma.

Stage 1BSlide94

Complications

Mortality 1-2%

Hemorrhage, shock, peritonitis, paralytic ileus, intestinal obstruction, thromboembolism

Bladder atony, cystitis, pyelitis, hydronephrosis,stenosis of ureter.

Stage 1B endocervicalSlide95

Chemotherapy

Cisplatinium based

Neoadjuvant chemotherapy, for preopt. large bulky tumors

Concurrent chemotherapy with RT for bulky advanced cancer.

Stage 2ASlide96

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

Stage 2B B A

1 Gray == 100radsSlide97

Radiotherapy +

Concurrent chemotherapy

Cis platinium 40mg/m2 weekly during external radiation.

Stage 3ASlide98

Interstial brachytherapy

Transperineal perforated templates with iridium-192 or iodine125

Advanced parametrial disease

Distorted anatomyPostopt. or postradiation recurrence

Stage 3BSlide99

Complications

Flare up PID

Diarrhoea, abdominal cramps, nausea, bowel bleed

Arteritis, fibrosis,Radiation proctitisSubacute intestinal obstructionFistulaAvascular necrosis femur neck

Menopausal symptomsStage 4ASlide100

5 year survival rates

Overall

Stage 1- 85%

Stage 1B 87-91% - node -ve 51-67% - node +veStage 2 - 60%Stage 3 - 33%Stage 4 – 10%

Radiotherapy Stage 1 - 80-90%Stage 2 - 55-70%Stage 3 - 30-35%Stage 4 - 10%Surgery Stage 1 - 70%Stage 2 - 45-50%