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INTRAEPITHELIAL

DISEASE OF THE
CERVIX

CERVICAL INTRAEPITHELIAL
NEOPLASIA

epithelial changes have the


appearance of invasive
cancer but were confined to
the epithelium
if untreated may lead to
cancer
Dysplasia
Squamous metaplasia should
not be diagnosed as CIN

Criteria for diagnosis of


intraepithelial neoplasia

cellular immaturity
cellular disorganization
nuclear abnormalities
increased mitotic activity

CERVICAL ANATOMY

columnar epithelium
lines the endocervical
canal
squamous epithelium
covers the exocervix
SquamoColumnar
Junction (SCJ) point
where they meet

SCJ

dynamic point that changes in response


to puberty, pregnancy, menopause and
hormonal stimulation
neonates SCJ located at the exocervix
menarche production of estrogen
causes vaginal epithelium to fill with
glycogen, lactobacilli act on glycogen to
lower the pH, stimulating the
subcolumnar reserve cells to undergo
metaplasia

Transformation
zone metaplasia
occurs in the
original SCJ towards
the external os and
over the columnar
villi
CIN is believed to
originate as a single
focus in the
transformation zone
at the advancing SCJ

Anterior lip - 2x as
likely to develop CIN
progress horizontally
to involve the whole
transformation zone
cervical clefts most
severe CIN lesions
extent of involvement
of cervical glands
significant therapeutic
implications because
the entire gland must
be destroyed to ensure
elimination of the CIN

CIN is most likely to begin either during


manarche or after pregnancy
oncogenic factors are introduced
through sexual intercourse
HPV plays an important role in the
development of CIN

Normal Transformation
Zone

4 layers:
1. basal layer single
row of immature cells
with large nuclei and a
small amount of
cytoplasm
2. parabasal layer 2-4
rows of immature cells
that have normal mitotic
figures and provide the
replacement cells for the
overlying epithelium

3. Intermediate layer 4-6


rows with larger amount
of cytoplasm
- intercellular bridges
differentiation of
glycogen production
occurs
4. Superficial layer 5-8
rows of flattened cells
with small uniform nuclei
and a cytoplasm filled
with glycogen
- form the basis for Pap
testing

columnar epithelium single layer


metaplastic epithelium found at the
SCJ, begins in the subcolumnar
reserve cells
- metaplastic process starts at the
tip of the columnar villi which are
exposed first to the acid vaginal
environment

Risk Factors
EPIDEMIOLOGIC CHARACTERISTICS
Early intercourse
Multiple sex partners
Early marriage
Early childbearing
Prostitution
Male factor
Socioeconomic status and race
STDs
Immune status (e.g. HIV)

Risk Factors
OTHER POTENTIAL FACTORS
OCP Use
Smoking
Vitamin C deficiency
Prior Radiation
In utero DES exposure
Lupus Erythematosus
Vitamin A, E and folate deficiency

Risk Factors

VIRAL RELATIONS
Papilloma virus (HPV)
Non-oncogenic (6,11,42,43,44)
Oncogenic
(16,18,31,33,35,39,45,51,52,56,58,59,6
8)
Herpes Virus
CMV

CIN 1 mitoses
immature
cells
present only on
UPPER
3rd
of
epithelium

CIN 2 MIDDLE 3rd

CIN 3 LOWER 3rd

and
are
the
the

HPV

primary cause of cervical


cancer

koilocytosis cytologic
changes of HPV

mild dysplasia high levels of


HPV DNA and capsid antigen
(indicate productive viral
infection in these koilocytic
cells)

CIN lesions become severe


koilocytes disappear

HPV copy numbers decrease >>>


capsid antigen disappears >>> HPV
DNA become integrated into the host
cell >>> essential for malignant
growth

Malignant transformation requires


the expression of E6 and E7
oncoproteins produced by HPV

HPV DNA is detected in most women


with cervical neoplasia

90% - intraepithelial neoplasia


attributed to HPV infection

Type 16 most common in invasive


cancer and CIN 2 and 3 [47%]
- most common in women with
normal cytology

HPV 16 not very specific


> 16% low grade lesions
> 14% normal cytology

HPV 18 more specific


> 23% invasive cancer
> 5% CIN 2 and 3
> 3% HPV and CIN 1
> <2% normal cytology

infection will clear in 915months


progression
> smoking
> contraceptive use
> infection with other STD
> nutrition
HPV vaccine efficacy >
85% for persistent
infection and 93% for
cytologic abnormalities

PAP test classification

Bethesda system for cytologic


reporting -1988

potentially premalignant squamous


lesions
1. ASC ASC-US, ASC-H
2. LSIL CIN 1, koilocytotic atypia
3. HSIL CIN 2, 3 & carcinoma in
situ

DIAGNOSIS

PAPANICOLAOU TEST
> reduced incidence of
cervical CA by 79%
> decreased mortality by
70%
> sensitivity in detecting
CIN 2&3 47-62%
> specificity 60-95%

Errors in PAP test

sampling lesion is too small to


exfoliate cells or device used did not
pick up the cells and transfer them to
the glass slide
preparation poor fixation on the glass
slide
- slide too thick and obscured by vaginal
discharge, blood or mucus
interpretation

Liquid based cytology 80% sensitvity

Pap Testing Frequency


ACOG

ACS

CTF

IAC

NCI

Start

18, start 20, start Start of


of sex
of sex
sex
activity activity activity

18,start Start of
of sex
sex
activity activity

18-35

annual

Annual
until 2
negq
3 yrs

annual Annual
if active of
active

After 2
negs
q 3 yrs

36-60

annual

q 3 yr,
After 2 annual
more of neg q
hi risk
5 yr

q 1 to 3
yr

Over 60 annual

q 3 yr,
2 neg annual
more of can
hi risk
stop

2 neg
can
stop

NEW ACOG RECOMMENDATIONS


FOR PAP SMEAR SCREENING

First Pap Smear: Approximately 3


years from coitarche or by age 21,
whichever comes first
Women up to age 30: every 2 years
Women 30 y.o. and older: negative
results for 3 consecutive pap
smears, may repeat every 3 years

Exceptions:

More frequent screening: HIV


positive, immunosuppressed,or
exposed to DES in utero, or with
previous diagnosis of CIN or
Cervical cancer
S/P Hysterectomy for benign
conditions with no history of
abnormal cell growth or cancer:
discontinue Pap smear

EXCEPTIONS

S/p hysterectomy with history of


abnormal cell growth/CIN 2-3:
annual Pap smear until 3
consecutive smears are negative,
then discontinue
What age to discontinue Pap smear?
65 y/o or 70 y/o with 3 consecutive
negative results and no abnormal
result in the past 10 years

2001 Bethesda System

specimen adequacy
satisfactory
unsatisfactory >> repeat 2-4 months
satisfactory but limited >> repeat 6-12
months

general categorizations:
Negative for intraepithelial lesions or
malignancy
- trichomonas, candida, bacterial
vaginosis, HSV
- reactive cellular changes,
atrophy
Epithelial cell abnormality

Screening Guidelines

PAP testing should occur every year


screening should start at age 21 or
within 3 years of onset of sexual
activity
screening after hysterectomy for
benign disease is not necessary
PAP test + HPV DNA testing - >30 yo
if (-) repeat after 3 years

COLPOSCOPY FINDINGS

Acetowhite epithelium
application of acetic acid
coagulates the proteins of the
nucleus and cytoplasm and makes
the proteins opaque and white
- dysplastic cells are mostly
affected

Leukoplakia white plaque


- layer of keratin on the surface of
the epithelium
- HPV, keratinizing CA, chronic
trauma from diaphragm, pessary
or tampon use, radiotherapy

Punctation dilated
capillaries terminating on
the surface appear from the
ends as a collection of dots
Mosaic terminal capillaries
surrounding roughly circular
or polygonal shaped blocks
of acetowhite epithelium
crowded together
- assoc with higher grade
lesions and CIN 2
Atypical vascular patternlooped, branching and
reticular vessels

Ablative therapy

no evidence of microinvasive or
invasive cancer on cytology,
colposcopy, endocervical curettage or
biopsy
lesion located in the ectocervix and
can be seen entirely
no involvement of the endocervix
with high-grade dysplasia as
determined by colposcopy and
endocervical curettage

Cryotherapy

Destroys the surface


epithelium of the cervix by
crystallizing the intracellular
water
-20 to -30 degrees
nitrous oxide and oxygen
c/p: cervical stenosis rare
acceptable:
1.) CIN, grade 1 or 2
2.) small lesion
3.) ectocervical location
4.) negative endocervical
sample
5.) no endocervical gland
involvement on biopsy

Laser ablation

used for treatment of CIN


very expensive

Loop electrosurgical excision


(LEEP)

Electrofulguration thermal damage


that leads to hemostatis
C/P : intraop hemorrhage, post
operative hge, cervical stenosis

CONIZATION
in women with HSIL by PAP test with:
1. limits of the lesion cant be visualized by
colposcopy
2. SCJ is not seen by colposcopy
3. ECC histologic findings are positive for CIN 2
or 3
4. substantial lack of correlation between
cytology, biopsy, and colposcopy
results
5. microinvasion is suspected based on biopsy,
colposcopy or biopsy result
6. Colposcopist unable to rule out invasive cancer

Complications of Excision

Cervical Stenosis
Infertility
Premature Birth (Cervical
Incompetence)

* 2 consecutive exams on patients


with LGSIL or 3 consecutive exams
on those with HGSIL are
negativeannual follow-up

HYSTERECTOMY

microinvasion
CIN 3 at limits of conization
specimen in selected patients
poor compliance with follow up
other gynecologic problems
requiring hysterectomy like fibroids,
prolapse, endometriosis and PID

Cervical Cancer

Bimodal peak incidence: 40 and 60 yo


Risk factors
Multiple sex partners
Early sexual activity
Multiparity
STDs
Male factor
Smoking (40 pack years)

Clinical Presentation

VAGINAL BLEEDING most important


symptom
> induced by sexual intercourse or
internal examination
> intermenstrual
VAGINAL DISCHARGE
Late Symptoms: back pain, loss of
appetite, wt loss

Histologic Types

SQUAMOUS (most common) 85-90%


Large cell (keratinizing, nonkeratinizing)
Small cell
Verrucous

*Prognosis related to:


1.Stage and size of lesion
2.Depth of invasion
3.Spread to lymph nodes

Histologic Types
Adenocarcinomas 10-15%
Endocervical/typical
Endometrioid
Clear cell
Adenoid cystic
Adenoma malignum
* prognosis-stage, size, grade, depth of
invasion

Histologic Types

Mixed
Adenosquamous
Glassy Cell

OLD FIGO STAGING OF


CERVICAL CANCER
Stage I
IA1

IA2
IB1
IB2

Carcinoma strictly confined to the


cervix
Cancer identified microscopically
Measured stromal invasion no greater
than 3 mm in depth and no wider than 7
mm
Measured stromal invasion greater than
3 mm and no greater than 5 mm in depth
And no wider than 7 mm
Clinical lesions no greater than 4 cm
in size
Clinical lesions greater than 4 cm in
size

Stage II

IIA
IIB
Stage III

IIIA
IIIB

Stage IV
IVA
IVB

Carcinoma extends beyond cervix, but


has not extended to pelvic wall;
involves vagina but not as far as
lower third
No obvious parametrial involvement
Obvious parametrial involvement
Extended to pelvic wall, no cancerfree space between tumor and pelvic
wall
No extension to pelvic wall, but
involves lower third of vagina
Extension to pelvic wall,
hydronephrosis or non-functioning
kidney due to the tumor
Extension beyond true pelvis
Spread to adjacent pelvic organs
Spread to distant organs

2008 FIGO STAGING FOR


CERVICAL CANCER
Stage I
IA

IA1

IA2

Cancer strictly confined to the cervix


Diagnosed microscopically, with deepest
invasion < or = 5 mm and largest extension
< or = 7 mm
Measured stromal invasion < or = 3 mm in
depth and horizontal extension of < or = 7
mm
Measured stromal invasion of > 3 mm and not
> 5 mm with an extension of not > 7 mm

IB

Clinically visible lesions limited to the


cervix or preclinical cancers > than stage
I

IB1

Clinically visible lesions < or = 4 cm in


greatest dimension
Clinically visible lesions > 4 cm in
greatest dimension

IB2

Stage II
IIA
IIA1
IIA2
IIB
Stage III

IIIA
IIIB

Cancer invades beyond uterus, but not the


pelvic wall or lower third of the vagina
Without parametrial invasion
Clinically visible lesions < or = 4 cm in
greatest dimension
Clinically visible lesions > 4 cm in
greatest dimension
With obvious parametrial involvement
Extension to pelvic wall, lower third of
vagina, hydronephrosis or non-functioning
kidney
Involves lower third of vagina, no pelvic
wall extension
Extension to pelvic wall and/or
hydronephrosis or non-functioning kidney

Stage IV

IVA
IVB

Extended beyond true pelvis or involved


the mucosa of the bladder or rectum
(biopsy proven). A bullous edema does
not permit a case to be alloted to
stage IV.
Spread of growth to adjacent organs
Spread to distant organs

Management Guidelines

Cervical cancer is diagnosed by BIOPSY. If


there is a gross lesion, no need for Pap
smear or fractional curettage
Staging is done CLINICALLY
Proctosigmoidoscopy and cytoscopy is done
if clinically indicated to rule out invasion
Special work-ups:CTScan, MRI,PET scan,
Bone scan
In selected cases, primary RAD HYS with
Pelvic node dissection is done (up to II A)

Management Guidelines

CHEMORADIATION (minimum std tx)


Primary Total hysterectomy with or
without BSO is NOT done in cervical
cancer

Primary Prevention

Monogamy
Delay in onset of sexual activity
Barrier contraception
Prompt and adequate tx of STDs

Natural History and Spread

Cervix Vagina Paracervical and


Parametrial Areas
Exophytic Growth- cauliflower-like extruding
from the cervix; abnormal bleeding or
staining
Endophytic- asymptomatic and deeply
invasive upon diagnosis (Barrel Shaped
Cervix);
Primary Path for distant spread- lymphatics
to the regional pelvic nodes

Initially- Cervical Ca primary nodes


(Pericervical, Presacral, internal and
external iliacs, obturator fossa
Secondary spread common iliac and
paraaortic nodes.
If the lower one third of the vagina is
involved median inguinal nodes

Hematogenous Spread

Lung
Liver
Bone

Follow Up

Reappearance of tumor 6 months or


more after therapy
Every 3 months for the 1st 2 yrs
Every 6 months from 3rd-5th year
Yearly thereafter
PE, Chest Xray, IVP or Abdominal Pelvic
CT

CERVICAL CA IN
PREGNANCY

Cervical cancer is the most common


malignancy in pregnancy

It is recommended that as part of routine


prenatal care, a pregnant woman
undergo a Pap smear at the first prenatal
visit as well as 6 weeks post-partum

Signs and symptoms

Watery vaginal discharge


Intermittent spotting
Post-coital bleeding
Pelvic pain or pressure
Rectal or urinary tract symptoms

Diagnosis

Diagnosing cervical cancer is essentially


done in the same manner as in the nonpregnant patient
However, pregnancy may mimic/mask
signs of cancer, possibly delaying
diagnosisthis shows the importance of
screening women for this disease.
Also, visualization of the cervix may be
compromised by a pregnant state.

Cyto-brush and liquid-based cytology


have drastically improved screening
leading to a decreased false negative
rate

Cervical biopsy should only be performed


on the worst visible lesion to prevent
bleeding complicationsand repeat
biopsies are generally discouraged
unless the lesion progresses.

Timing of diagnosis dictates much of the


treatment strategy

Before 20 weeks, the option to terminate


the pregnancy is available

General conceptsin early lesions or


minimally invasive disease, waiting for
fetal maturity and delaying cancer
treatment is standard

LSIL or CIN has a relatively small risk of


progression during the course of the
pregnancy
It takes 7 years for LSIL to progress to
cervical cancer and 4 years for HSIL
Conservative management for
intraepithelial lesions.

Close follow up with repeat cytology and


colposcopy is recommended throughout
gestation.
Cervical conization is only performed
with suspicion of invasive cancer due to
risks such as hemorrhage, miscarriage,
fetal loss, and increased perinatal death
Conization also increases the incidence
of premature ROM in subsequent
pregnancies.

Delivery, in a sense is the beginning of therapy for


most mothers
Vaginal delivery is contraindicated when a gross
tumor exists (IB) due to unfavorable maternal
outcomes

Radical Trachelectomy with Pelvic


Lymphadenectomyremoval of cervix with
adequate uninvolved margins while maintaining
the uterine body (this procedure is designed to
preserve fertility)

Radiationinduces abortion

Delayed therapy in advanced cervical cancer is of


unclear benefit.

SOCIETY OF GYNECOLOGIC ONCOLOGISTS


OF THE PHILIPPINES

CLINICAL PRACTICE
GUIDELINES
FOR THE
OBSTETRICIANGYNECOLOGIST
2010

LEVEL

DEFINITION

Evidence obtained from at least one properly randomized


controlled trial

II-1

Evidence obtained from well-designed controlled trials without


randomization

II-2

Evidence obtained from well-designed cohort or case-control


analytic studies, preferably from more than one center or
research group

II-3

Evidence obtained from multiple time series with or without the


intervention.

III

Opinions of respected authorities, based on clinical


experience; descriptive studies and case reports or reports of
expert committees.

GRADE

DEFINITION

There is good evidence to support the recommendation of the


practice.

There is fair evidence to support the recommendation of the


practice.

There is insufficient evidence to recommend for or against the


inclusion of the practice.

There is fair evidence to support the recommendation that the


practice be excluded.

There is good evidence to support the recommendation that


the practice be excluded.

GPP

A good practice point (GPP) is a recommendation for best


practice based on the experience of the Working Group.

CERVICAL CANCER

Risk Factors/
Co-factors

CERVICAL CANCER: Risk factors


Human papilloma virus (HPV)
Statement 1 infection is the necessary cause
(Level II-2,
of
cervical
cancer.
Grade A)
HPV
Infection

Franceschi S. The IARC commitment to cancer prevention: The example of


papillomavirus and cervical cancer. Recent Results in Cancer Research
2005;166:277297.
Bosch FX, Lorincz A, Muoz N, Meijer CJLM, Shah KV. The causal relation between
human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244-65.
Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH,
Moreno V, Kurman R, Shah KV. Prevalence of human papillomavirus in cervical
cancer: a worldwide perspective. International biological study on cervical
cancer (IBSCC) study group. J Natl Cancer Inst 1995;87:796-802.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders
PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of
invasive cervical cancer worldwide. J Pathol 1999;189:12-9

CERVICAL CANCER: Risk factors


Supporting Statements:
Statement 1
(Level II-2,
IARC Meta-analysis (10,058 Cxca
Grade A)
cases; 85 published studies)
HPV 16 (51%) HPV 18 (16.2%)
High risk HPV types
HPV
(types16,18,45,31,58,52,35,59,56,51,
Infection
68,39,82,73,66,70)

CERVICAL CANCER: Cofactors

Statement 2:
(Level II-2,
Grade A)
High parity

Parity of 7 or more
increases the risk for cervical
cancer.
Muoz N, Franceschi S, Bosetti C, et al. Role of parity and
human papillomavirus in cervical cancer: the IARC
multicentric case-control study. Lancet 2002 Mar
30;359(9312):1093-101.
International Collaboration of Epidemiological Studies of
Cervical Cancer. Cervical carcinoma and reproductive
factors: Collaborative reanalysis of individual data on
16,563 women with cervical carcinoma and 33,542 women
without cervical carcinoma from 25 epidemiological
studies. Int J. Cancer 2006;119:1108-1124

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 2: (HPV +) 7 full term vs nulliparous
(Level II-2,
(Odds ratio 3.6, 95% CI 2.7-5.5)
Grade A)
Maintenance of transformation zone
High parity

CERVICAL CANCER: Cofactors


Long-term use of oral
contraceptive pills (OCPs) could
increase the risk of cervical cancer by
Statement 3: up to fourfold in women with HPV
(Level II-2,
infection.
Grade A)
OCP use

Moreno V, Bosch FX, Muoz N, et al. Effect of oral contraceptives


on risk of cervical cancer in women with human papillomavirus
infection: the IARC multicentric case-control study. Lancet
2002;359(9312):108592.
Smith JS, Green J, Berrington dG, Appleby P, Peto J, Plummer M,
Franceschi S, Beral V. Cervical cancer and use of hormonal
contraceptives: a systematic review. Lancet 2003; 361:1159-67.
nternational Collaboration of Epidemiological Studies of Cervical
Cancer. Cervical cancer and hormonal contraceptives:
collaborative reanalysis of individual data for 16,573 women with
cervical cancer and 35,509 women without cervical cancer from
24 epidemiological studies. Lancet 2007;370:1609-1621.

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 3:
10 case control studies (pooled)
(Level II-2,
5 years use vs never use
Grade A)
(RR 1.90, 95% CI 1.69 2.13)
risk declined after use; 10 years of
OCP use
non use, equivalent to non users
Promotes integration of HPV DNA

CERVICAL CANCER: Cofactors


The risk of squamous cell carcinoma
increases in current smokers with
Statement 4: the number of cigarettes smoked
(Level II-2,
per day and with younger age at
Grade A)
starting smoking.
Smoking

International Collaboration of Epidemiological Studies of Cervical


Cancer. Carcinoma of the cervix and tobacco smoking:
collaborative re-analysis of individual data on 13,541 women with
carcinoma of the cervix and 23,017 women without carcinoma of
the cervix from 23 epidemiological studies. Int J Cancer
2006;118:1481-1495.
Giulian AR, Sedjo RL, Roe DJ, Harri R, Baldwi S, Papenfuss MR, et al.
Clearance of oncogenic human papillomavirus (HPV) infection:
effect of smoking. Cancer Causes Control 2002;13:83946

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 4: Current smokers
(Level II-2,
(RR 1.60; 95% CI 1.48 1.73)
Grade A)
Past smokers
(RR 1.12; 95% CI 1.01 1.25)
Smoking
Tumor type: Squamous Cell CA
Promotes persistent HPV infection
Tobacco related carcinogen

CERVICAL CANCER: Cofactors


Women who are co-infected with
HPV and another sexually
Statement 5: transmitted agent, such as
(Level II-2,
Chlamydia trachomatis or Herpes
Grade B)
simplex virus 2 (HSV-2), are more
likely to develop cervical cancer than
Co-infection are women who are not co-infected.
with other
Smith JS, Munoz N, Herrero R, Eluf-Neto J, Ngelangel C, Franceschi
STDs
S, et al. Evidence for Chlamydia trachomatis as a human
papillomavirus cofactor in the etiology of invasive cervical cancer
in Brazil and the Philippines. J Infect Dis 2002;185:32431.
Smith JS, Herrero R, Bosetti C, et al. Herpes simplex virus-2 as a
human papillomavirus cofactor in the etiology of invasive cervical
cancer. J of the NCI Nov 2002;94(21):16041613

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 5: Chlaymdia trachomatis
(Level II-2,
(OR 2.1; 95% CI 1.1 4.0)
Grade B)
HSV-2 infection: 3 fold increase in
Co-infection risk
with other
STDs

CERVICAL CANCER: Cofactors


Women infected with human
immunodeficiency virus (HIV) are
more readily infected with high
risk HPV types and are more likely
Statement 6: to develop cervical cancer than HIV(Level III,
negative women in the same age
Grade C)
category.
HIV

Clifford GM et al, HPV and HIV study group: Human papillomavirus


types among women infected with HIV: a meta-analysis. AIDS.
2006 Nov 28;20(18):2337-44.
Palefsky JM, Holly EA. Chapter 6: Immunosuppressionand coinfection with HIV. J Natl Cancer Inst Monogr 2003;41-6.
Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated
cancers in patients with human immunodeficiency virus infection
and acquired immunodeficiency syndrome. J of the NCI
2000;92:1500-10

CERVICAL CANCER: Cofactors


Supporting Statements:
41% of HIV patients had >1 HPV
Statement 6: type of infection vs 7% in general
(Level III,
population
Grade C)
HIV

HPV types 18, 51, 52, 58

CERVICAL CANCER: Cofactors

Statement 7:
(Level II-2,
Grade A)
Early coitus

Early age at first intercourse

increases the risk for cervical


cancer (age < 14).
International Collaboration of Epidemiological Studies of
Cervical Cancer. Cervical carcinoma and sexual behaviour:
collaborative reanalysis of individual data on 15,461
women with cervical carcinoma and 29,164 women
without cervical carcinoma from 21 epidemiological
studies. Cancer Epidemiol Biomarkers Prev. 2009 Apr;
18(4):1060-9

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 7: Ist coitus (14 yo vs 25 yo)
(RR 3.52; 95% CI 3.04 4.08)
(Level II-2,
Grade A)
Early coitus

CERVICAL CANCER: Cofactors


The risk of invasive cervical
Statement 8: carcinoma increased with lifetime
(Level II-2,
number
of
sexual
partners
Grade B)
(6 or more).
Six or more
lifetime
sexual
partners

International Collaboration of Epidemiological Studies of


Cervical Cancer. Cervical carcinoma and sexual behaviour:
collaborative reanalysis of individual data on 15,461
women with cervical carcinoma and 29,164 women
without cervical carcinoma from 21 epidemiological
studies. Cancer Epidemiol Biomarkers Prev. 2009
Apr;18(4):1060-9

CERVICAL CANCER: Cofactors


Supporting Statements:

Statement 8:
(Level II-2,
Lifetime partners (6 vs 1)
Grade B)
(RR 2.27; 95% CI 1.98 2.61)
Six or more
lifetime
sexual
partners

CERVICAL CANCER: Cofactors


Early age at first full term
Statement 9:
pregnancy (age < 17) increases
(Level II-2,
the risk for invasive cervical
Grade B)
cancer.
Early age at
first full term
pregnancy

International Collaboration of Epidemiological Studies of


Cervical Cancer. Cervical carcinoma and reproductive
factors: Collaborative reanalysis of individual data on
16,563 women with cervical carcinoma and 33,542 women
without cervical carcinoma from 25 epidemiological
studies. Int J Cancer 2006;119:1108-1124

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 9:
(Level II-2,
Age of 1st G1 (<17 yo vs 25 yo)
Grade B)
(RR 1.77; 95% CI 1.26 2.51)
Early age at
first full term
pregnancy

CERVICAL CANCER: Cofactors


Male circumcision is associated with
a reduced risk of penile HPV
Statement 10: infection and, in the case of men
(Level II-2,
with a history of multiple sexual
Grade B)
partners, a reduced risk of cervical
cancer in their current female
Male
partners.
circumcision
Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de
Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith
JS, Herrero R, Moreno V.
Franceschi S. Male circumcision, penile human
papillomavirus infection, and cervical cancer in female
partners. N Engl J Med 2002; 346:1105-12

CERVICAL CANCER: Cofactors


Supporting Statements:
Statement 10: Circumcised vs non-circumcised
(Level II-2,
(OR 0.37; 95% CI 0.16 0.85)
Grade B)
Male
circumcision

6 partners; C vs NC
(OR 0.42; 95% CI 0.23 0.79)

CERVICAL CANCER: Cofactors

Statement 11:
(Level II-2,
Grade A)

No prior
screening

The risk of developing invasive


cervical cancer is three to ten
times greater in women who
have not been screened.
CDoes screening by "Pap" smears help prevent cervical cancer? A
case-control study. Lancet 1979;2(8132):larke EA, Anderson TW. 14.
La Vecchia C, Franceschi S, Decarli A, et al. "Pap" smear and the
risk of cervical neoplasia: quantitative estimates from a casecontrol study. Lancet 1984;2(8406):779-82.
Herrero R, Brinton LA, Reeves WC, et al. Screening for cervical
cancer in Latin America: a case-control study. Int J Epidemiol
1992;21(6):1050-6.
Screening for squamous cervical cancer: duration of low risk after
negative results of cervical cytology and its implication for
screening policies. IARC Working Group on evaluation of cervical
cancer screening programmes. Br Med J (Clin Res Ed)
1986;293(6548):659-64

CERVICAL CANCER: Cofactors


Statement 12:
(Level III,
Grade C)

Low socioeconomic
status

Low socio-economic status (SES) is


recognized as a risk factor for many
health problems, including cervical
cancer, particularly in low-resource
settings.
Dos Santos IS, Beral V. Socio-economic
differences in reproductive behaviour. IARC
Scientific Publications 1997;138:285308

Primary Prevention

CERVICAL CANCER: Primary prevention

Statement 1:
(Level II-2,
Grade A)
Abstinence
from sexual
activity

Total abstinence prevents


HPV infection.
Fairley CK, Chen S, Tabrizi SN, Leeton K, Quinn MA, Garland SM.
The absence of genital human papillomavirus DNA in virginal
women. International Journal of STD & AIDS 1992; 3(6):414-417.
Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA.
Genital human papillomavirus infection: incidence and risk factors
in a cohort of female university students. American Journal of
Epidemiology 2003; 157(3):218-226.
Herrero R, Hildesheim A, Bratti C, et al. Population-based study of
human papillomavirus infection and cervical neoplasia in rural
Costa Rica. J Natl Cancer Inst 2000;92(6):464-74

CERVICAL CANCER: Primary prevention

Statement 2:
(Level II-2,
Grade A)
Mutual
Monogamy

Lifetime mutual monogamy


prevents HPV infection.
Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural
history of cervicovaginal papillomavirus infection in young
women. New England Journal of Medicine 1998;
338(7):423-428.
Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky
LA. Genital human papillomavirus infection: incidence and
risk factors in a cohort of female university students.
American Journal of Epidemiology 2003; 157(3):218-226

CERVICAL CANCER: Primary prevention


Statement 3:
(Level II-2,
Grade A)
Barrier
protection
during
sexual
intercourse

Consistent and correct use


of barrier protection
decreases cervical cancer
incidence.
Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of
genital human papillomavirus infection in young women. N Engl J
Med 2006;354(25):2645-54.
Lytle CD, Routson LB, Seaborn GB, Dixon LG, Bushar HF, Cyr WH.
An in vitro evaluation of condoms as barriers to a small virus.
Sexually Transmitted Diseases 1997; 24(3):161-164.
Parazzini F, Negri E, La Vecchia C, et al. Barrier methods of
contraception and the risk of cervical neoplasia. Contraception
1989;40(5):519-30.
Hildesheim A, Brinton LA, Mallin K, et al. Barrier and spermicidal
contraceptive methods and risk of invasive cervical cancer.
Epidemiology 1990;1(4):266-72

CERVICAL CANCER: Primary prevention

Statement 4:
(Level I,
Grade A)
HPV
Vaccination

Vaccination against
HPV 16/18 is efficacious
against persistent HPV
infection and CIN 2+.
Munoz N, Manalastas R Jr., Pitisuttithum. Safety, immunogenicity,
and efficacy of quadrivalent human papillomavirus (types 6, 11,
16, 18) recombinant vaccine in women aged 24-45 years: a
randomised, double-blind trial. Lancet 2009 Jun 6;373(9679):194957.
Paavonen J, Naud P, Salmeron J, et al. Efficacy of human
papillomavirus (HPV) 16/18 AS04-adjuvanted vaccine against
cervical infection and precancer caused by oncogenic HPV types
(PATRICIA): final analysis of a double-blind, randomised study in
young women. Lancet 2009 Jul 25;374(9686):301-14

CERVICAL CANCER: Primary prevention


Oral supplementation with
folic acid, beta carotene, or
Statement 5:
vitamin C does not enhance
(Level II-2,
regression of premalignant
Grade B)
cervical lesions.
Supplements

Garca-Closas R, Castellsagu X, Bosch X, Gonzlez CA.


The role of diet and nutrition in cervical carcinogenesis: a
review of recent evidence.Int J Cancer 2005 Nov
20;117(4):629-37.
Sasieni P. Chemoprevention of cervical cancer. Best Pract
Res Clin Obstet Gynaecol 2006 Apr; 20(2):295-305
Ghosh C, Baker JA, et al. Dietary intakes of selected
nutrients and food groups and risk of cervical cancer. Nutr
Cancer 2008;60(3):331-41

Secondary
Prevention

CERVICAL CANCER: Secondary prevention

Screening via regular


gynecologic examinations and
Statement 1:
cytologic
test
(Pap
smear)
with
(Level II-2,
treatment of precancerous
Grade A)
abnormalities decreases the
The
incidence and mortality of
Papanicolaou
cervical
cancer.
(Pap)Smear
Screening for squamous cervical cancer: duration of low
risk after negative results of cervical cytology and its
implication for screening policies. IARC Working Group on
evaluation of cervical cancer screening programmes. Br
Med J (Clin Res Ed) 1986;293(6548):659-64

CERVICAL CANCER: Secondary prevention

Liquid based cytology offers


the advantage of doing HPV
Statement 2: testing on the same preparation.
(Level II-2,
However, it is not more
Grade B)
sensitive or specific
than conventional pap smear.
Liquid based
cytology
Hartmann KE, Hall SA, Nanda K, et al. Screening for
Cervical Cancer. Rockville, Md: Agency for Health Research
and Quality, 2002.
Coste J, Cochand-Priollet B, de Cremoux P, et al. Cross
sectional study of conventional cervical smear, monolayer
cytology, and human papillomavirus DNA testing for
cervical cancer screening. BMJ 2003;326(7392):733

CERVICAL CANCER: Secondary prevention

Statement 3:
(Level I,
Grade A)
Visual
Inspection
with Acetic
Acid

In low resource settings,


visual inspection with acetic
acid (VIA) is an acceptable
alternative to Pap smear.
Sankaranarayanan R, Esmy PO, Rajkumar R, et al. Effect of
visual screening on cervical cancer incidence and mortality
in Tamil Nadu, India: a cluster-randomised trial. Lancet
2007;370(9585): 398-406.
Denny L, Kuhn L, De Souza M, et al. Screen-and-treat
approaches for cervical cancer prevention in low-resource
settings: a randomized controlled trial. JAMA
2005;294(17):2173-81

CERVICAL CANCER: Secondary prevention

Statement 4:
(Level II-2,
Grade A)
When to
start
screening

Screening should begin


approximately 3 years after
the onset of vaginal
intercourse but not earlier
than 21.
Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N, et al.
The natural history of human papillomavirus infection as measured
by repeated DNA testing in adolescent and young women. J Pediatr
1998;132:27784.
Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Incidence and
duration of cervical human papillomavirus 6, 11, 16, and 18
infections in young women: an evaluation from multiple analytic
perspectives. Cancer Epidemiol Biomarkers Prev 2007;16:70915
Domingo E, Dy Echo A. Epidemiology, prevention and treatment of
cervical cancer in the Philippines. J Gynecol Oncol Mar
2009;20(1):11-16

CERVICAL CANCER: Secondary prevention

Annual screening with


conventional cervical cytology
Statement 5: smears, or biennial screening
(Level II-3,
using liquid based cytology, is
Grade A)
recommended until age 30
years.
Screening
interval

Sawaya GF, McConnell KJ, Kulasingam SL, Lawson HW, Kerlikowske


K, Melnikow J, et al. Risk of cervical cancer associated with
extending the interval between cervical cancer screenings. N Engl J
Med 2003;349:15019.
Screening for squamous cervical cancer: duration of low risk after
negative results of cervical cytology and its implication for
screening policies. IARC Working Group on evaluation of cervical
cancer screening programmes. Br Med J 1986;293:65964

CERVICAL CANCER: Secondary prevention


At or after age 30 years, a woman
Statement 5: who has had three consecutive,
(Level II-3,
technically satisfactory
Grade A)
normal/negative for intraepithelial
lesions or malignancy cytology results
Screening
may undergo screening every 2 to 3
interval
years using either conventional or
liquid based cytology.
(continuation)

Sawaya GF, McConnell KJ, Kulasingam SL, Lawson HW, Kerlikowske


K, Melnikow J, et al. Risk of cervical cancer associated with
extending the interval between cervical cancer screenings. N Engl J
Med 2003;349:15019.
Screening for squamous cervical cancer: duration of low risk after
negative results of cervical cytology and its implication for
screening policies. IARC Working Group on evaluation of cervical
cancer screening programmes. Br Med J 1986;293:65964

CERVICAL CANCER: Secondary prevention

Statement 6:
(Level I to II2, Grade A)
Screening
interval

Women aged 30 years and older who have


had three consecutive negative cervical
cytology screening test results and who have
no history of CIN 2 or CIN 3, are not HIV
infected, are not immunocompromised,
and were not exposed to diethylstilbestrol
in utero may extend the interval between
cervical cytology examinations to every 3
years.
Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening
with age: population based case-control study of prospectively
recorded data. BMJ 2009;339:b2968.
Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C,
et al. Accuracy of liquid based versus conventional cytology: overall
results of new technologies for cervical cancer screening:
randomised controlled trial. BMJ 2007;335:28

CERVICAL CANCER: Secondary prevention


Women treated in the past for CIN 2-3
Statement 7: or gynecologic cancers remain at risk
(Level II-2 to for persistent or recurrent disease for
III, Grade B) at least 20 years after treatment and
after initial post treatment surveillance,
and should continue to have annual
Women
screening for at least 20 years.
treated for
CIN2,3
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ,
Solomon D. 2006 consensus guidelines for the
management of women with cervical intraepithelial
neoplasia or adenocarcinoma in situ. 2006 American
Society for Colposcopy and Cervical Pathology-sponsored
Consensus Conference. Am J Obstet Gynecol
2007;197:3405

CERVICAL CANCER: Secondary prevention

In women who have had a total


Statement 8: hysterectomy for benign
(Level II-2,
indications and have no prior
Grade B)
history of high grade CIN, routine
cytology testing should be
When to
discontinue discontinued.
screening

Stokes-Lampard H, Wilson S, Waddell C, Ryan A,


Holder R, Kehoe S. Vaginal vault smears after
hysterectomy for reasons other than malignancy: a
systematic review of the literature. BJOG
2006;113:135465

CERVICAL CANCER: Secondary prevention

Statement 9: Discontinue cervical cancer


(Level II-2,
screening between 65 years and 70
Grade B)
years of age in women who have
three or more negative cytology
When to
test results in a row and
discontinue no abnormal test results in the past
screening
10 years.
Sawaya GF, Grady D, Kerlikowske K, Valleur JL, Barnabei
VM, Bass K, et al. The positive predictive value of cervical
smears in previously screened postmenopausal women: the
Heart and Estrogen/progestin Replacement Study (HERS).
Ann Intern Med 2000;133:94250

CERVICAL CANCER: Secondary prevention

Statement 10: Co-testing using the


(Level II-3,
combination of cytology plus
Grade A)
HPV DNA testing is an
Co testing in
Women 30
years old and
above

appropriate screening test for


women older than 30 years.
Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A,
Munk C, et al. Long term predictive values of cytology
and human papillomavirus testing in cervical cancer
screening: Joint European cohort study. Joint European
Cohort Study. BMJ 2008;337:a1754.

CERVICAL CANCER: Secondary prevention


Statement 10: Supporting Statements:
(Level II-3,
Low risk women, 30 yo, negative
Grade A)
cytology and HPV DNA test
rescreen 3 years after
Co testing in
Women 30
years old and
above

CERVICAL CANCER: Secondary prevention


Testing for HPV DNA currently is
used in cervical cancer screening as
a triage test to stratify risk to
Statement 11: women aged 21 years and older with
(Level III,
a cytology diagnosis of ASC-US and
Grade B)
postmenopausal women with a
cytology diagnosis of LSIL.
HPV Testing
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson
EJ, Solomon D. 2006 consensus guidelines for the
management of women with abnormal cervical cancer
screening tests. 2006 American Society for Colposcopy
and Cervical Pathology-sponsored Consensus
Conference. Am J Obstet Gynecol 2007;197:34655.
Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G,
Dillner J. clinical applications of HPV testing: a summary
of meta-analyses. Vaccine 2006;24(suppl 3):S3/7889

CERVICAL CANCER: Secondary prevention

Statement 12:
(Level III,
Grade C)
Annual
gynaecologic
examination

Annual gynecologic
examination is recommended
regardless of the frequency of
screening.
American College of Obstetricians and
Gynecologists. ACOG Practice Bulletin number
109, December 2009: cervical cytology
screening. Obstet Gynecol 2009;114:1409-1420.

CERVICAL CANCER: Secondary prevention

Women who have been


Statement 13: immunized against HPV 16
(Level III,
and HPV 18 should be
Grade C)
screened by the same regimen
as non-immunized women.
Screening of
HPV
immunized
women

American College of Obstetricians and Gynecologists.


ACOG Practice Bulletin number 109, December 2009:
cervical cytology screening. Obstet Gynecol
2009;114:1409-1420.
Wright TC, Van Damme P, Schmitt HJ, Meheus A.Chapter
14: HPV vaccine introduction in industrialized countries.
Vaccine 2006;24(
suppl 3):S3/12231

CERVICAL CANCER: Secondary prevention

Statement 14:
(Level III,
Grade C)
Pap test in
patients with
HIV infection

A Pap test should be obtained twice


in the first year after diagnosis of HIV
infection and, if the results are
normal, annually thereafter.
2006 CDC Guidelines on Sexually transmitted infections
(MMWR Recommendations and Reports,
http://www.cdc.gov/std/treatment/2006 accessed april 2
9
, 2010
De Sanjose S, Palefsky J. Cervical and anal HPV infections
in HIV positive women and men. Virus Research
89(2):201211 November 2002.
Clarke B, Chetty R. Postmodern cancer: the role of human
immunodeficiency virus in uterine cervical cancer.
Molecular Pathology 55(1):1924 February 2002