Transcript Screening tests - Aurora

“A European network on cervical cancer surveillance and
control in the new Member States - AURORA”
1st Module: Scientific Background for Healthcare Professionals
Partners
www.aurora-project.eu
This publication arises from the project «AURORA» which has received funding from
the European Union in the Framework of the Health Programme.
Index
1. Cervical cancer epidemiology
2. Introductory issues about STIs and HPV infection – transmission
3. Diagnosis of HPV infection. Screening tests (cervical cytology; liquid-based
cervical cytology; visual inspection; colposcopy; HPV DNA testing)
4. How to organise a population based screening programme
5. Prevention of infection: vaccination
6. Diagnosis and treatment of cervical cancer disease
Cervical cancer epidemiology
1. Cervical cancer epidemiology
•
•
Rates are lowest in Western Asia, Northern America and Australia/New Zealand (ASRs less
than 6 per 100 00). Cervical cancer remains the most common cancer in women only in
Eastern Africa, South-Central Asia and Melanesia.
Using crude incidence rates, cervical cancer ranks as the 2nd most frequent cancer among
women between 15 and 44 years of age.
• Cervical cancer is the third most common cancer in
women, and the most common in 15-44 ys. female
population, with an estimated 530 000 new cases
in 2008. More than 85% of the global burden
occurs in developing countries, where it accounts
for 13% of all female cancers.
• High-risk regions are Eastern and Western Africa
(ASR-age standardised rate /incidence per 100000
women greater then 30 per 100,000), Southern
Africa (26,8 per 100 000), South-Central Asia (24,.6
per 100 000), South America and Middle Africa
(ASRs 23,9 and 23,0 per 100 000 respectively).
http://globocan.iarc.fr/factsheet.asp: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and
Mortality Worldwide: IARC CancerBase No. 10 International Agency for Research on Cancer; 2010.
Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence in 2008 for 27 sites in the adult population, submitted.
Mortality
Overall, the mortality incidence
ratio is 52%, and cervical cancer is
responsible for 275.000 deaths in
2008, about 88% of which occur in
developing countries: 53.000 in
Africa, 31.700 in Latin America
and the Caribbean, and 159.800 in
Asia.
http://globocan.iarc.fr/factsheet.asp: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and
Mortality Worldwide: IARC CancerBase No. 10 International Agency for Research on Cancer; 2010.
Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence in 2008 for 27 sites in the adult population, submitted.
Cervical cancer incidence
Worldwide
Estimated incidence from Cervix uteri cancer in 2008 ;
Age Standardised Rate (European) per 100,000
Europe
European Cancer Observatory
http://eu-cancer.iarc.fr/cancer-14-cervix-uteri.html,en
Cervical cancer mortality
Worldwide
Estimated mortality from Cervix uteri cancer in
2008 ;
Age Standardised Rate (European) per 100,000
Europe
European Cancer Observatory
http://eu-cancer.iarc.fr/cancer-14-cervix-uteri.html,en
Estimated age-standardized rates in 2008 per 100 000
Europe
Worldwide
Cervical cancer in EU
Within the EU, wide variation is observed. The mortality was
highest in Romania (world standardised rates of 13,7/100.000
women/year) and lowest in Finland (1,1/ 100.000/ year).
The burden of cervical cancer is particularly high in the new
member states. With the exception of Malta, all 11 other newly
acceded members have higher incidence and mortality rates for
cervix cancer than the 15 countries belonging to the European
Union before the expansion in 2004 and 2007.
Arbyn M et al., 2007a & b.
HPV infection
and transmission
Introductory issues about STIs and HPV infection
In 2008 Harald zur Hausen (German Cancer Research Centre, Heidelberg, Germany) Nobel Prize "for his discovery of human papilloma viruses causing cervical cancer"
•
•
•
•
•
The genetic map of HPBV16 genome
(Doorbar J. Clinical Science, 2006)
HPV are small, non-enveloped, DNA viruses with diameter
of 52–55 nm.
The HPV genome contains around 8000 pb and consists of:
Early region: encodes for 6 proteins - E6 and E7(red) are
transforming oncoproteins; others (green) are required for
viral replication
Late region: encodes for 2 viral capsid proteins – L1 and L2
(yelow); L1 ORF - most conserved and used for
identification of new types (L1 protein is used to make
virus-like particles (VLPs) used in the currently available
vaccines.
Long Control Region (LCR): sequences that control
transcription of the viral genome
Electron micrograph of HPV16 L1 VLPs
(J.Schiller, 2000)
HPV Transmission
● Through sexual intercourse
● Without sexual intercourse – through genital contact with an infected person
● In rare cases - from mother to baby during vaginal delivery.
● HPV can be passed even when the infected partner has no signs or symptoms.
Not all HPV infections will lead to cervical cancer. Most of the HPV
infection will clear spontaneously or after treatment. Cytologic screening
will allow early detection and effective intervention, but cervical cancer
can not develop without a persistent HPV infection!
(http://www.cdc.gov/std/hpv/commonclinicians/ClinicianBro.txt).
◄ Schiffman & Castle, 2005
HPV Related Cervical
Disease by Age
Risk Factors
HPV infection is the necessary cause of cervical cancer, but HPV infection is
not sufficient to cause cervical cancer. Most of women infected with an
oncogenic HPV type never develop cervical cancer, therefore additional
factors contribute to cervical cancer development.
Age of sexual debut, lifetime number of sexual partners, history of sexually
transmitted infections, and other characteristics of sexual activity are linked
to the likelihood of HPV infection, but are not cofactors for the progression
from HPV infection to cervical cancer.
Parity, use of oral contraceptives, tobacco smoking, immunosuppression
(particularly related to HIV), infection with other sexually transmitted
diseases, and poor nutrition, have been associated, to various extents, with
the development of invasive cervical cancer.
http://screening.iarc.fr/doc/RH_fs_risk_factors.pdf
◄ The key
events that
occur following
infection.
This patterns of
gene expression is
apparent in lowgrade squamous
intraepithelial
neoplasia (LSIL).
Doorbar J. Clinical
Science (2006)110,
525-541
HPV infection
Transient infection - asymptomatic,
Persistent infection - is not cleared
subclinical
• no clinical consequences in
immunocompetent individuals.
• incubation period – unclear, probably
weeks to months for genital warts,
several months to years for cervical
cellular abnormalities.
by the immune system - persistently
detectable HPV DNA.
factors:
• older age,
• high-risk HPV types,
• immunodeficiency.
Classification of Oncogenic Risk by HPV Genotype
There are over 100 different types of HPVs. Over 30 types are involved in genital infections.
Based on their oncogenic power they are divided in “low risk” (LR) and “high risk” (HR).
High-risk (HR)
oncogenic
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,59, 66, 68, 69, 73,82
Low-risk (LR)
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, 89
•
HR types cause cervical intraepithelial neoplasia (CIN) and invasive cancer. 99% of all cervical
cancer cases are caused by HPV infection.
•
Two HR types, HPV16 and 18, cause over 70% of cervical cancers, with type 16 having the
greatest oncogenic potential.
•
The LR types such as HPV6 and HPV11 are associated with condyloma acuminate and LSIL.
•
The distribution of HPV types varies among geographical regions, but the dominant oncogenic
type in all regions is HPV-16
HPV types in women with normal cytology
Cervical HPV prevalence in 5 continents: meta-analysis of 1 million women with
normal cytological findings
• Although the prevalence of
HPV types varied across
countries, types 16, 18, 31,
52, and 58 were consistently
among the 10 most common
in all regions.
• The most prevalent HPV
types in Europe are types 16,
31, 18, 39, 33 and 66.
◄Bruni L et al. J Infect Dis. 2010, 202, 789-99
The most relevant HPV types in cervical cancer
by histology groups
In two large studies of
HPV types in cervical
cancer specimens, the
most common types
were 16, 18, 45, 58, 31,
33, 52, and 35.
◄ HPV Today, slide №22, april 2011
Recent meta-analyses show that the most common cervical HPV types in women with normal
cytology and the types associated with cervical cancer are similar worldwide. These findings are
important for evaluating the impact of the current prophylactic vaccines as well as for developing new
vaccines.
Natural history of HPV infection
Normal
Infection
Clearance >90%
HPV
infection
Progression 10%
Regression 70%
Precancer (LSIL)
Progression 30%
Transient infection
Within 1
year
Persistent infection
Up to 5
years
Regression 30 %
Precancer (HSIL)
Invasion
Cervical
Cancer
While persistent infection with high-risk
types is considered necessary for the
development of cervical cancer, it is not
sufficient, as the vast majority of women
with high-risk HPV infection do not
develop cancer.
>10 years
LSIL - Low-grade cervical lesions;
HSIL – High- Low-grade cervical lesions
1. Koutsky, Am J Med 1997. 2. Feoli-Fonseca et al. J med Virol 2001. 3. Liaw et al. JNCI 1999. 4. Clifford et al. Int Papillomvirus Conference 2004. 5. Globocan 2000. 6. Sawaya et al.
NEJM 2003. 7. Mark Schiffman J Natl Cancer Inst Monogr 2003.
.
Age-specific incidence of HPV infection and cervical cancer
(Netherlands data)
Peak 1
Peak 2
20
Oncogenic HPV (%)
18
16
15
14
12
10
10
8
6
5
4
2
0
Age-standardised incidence
rate for cervical cancer (per
100,000)
20
0
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64
Age (years)
HPV infection precedes cervical cancer by some decades. The age-specific incidence rate (ASR) of cervical
cancer shows a rising trend in the 20-40 years age group followed by a plateau or smooth increase. The agespecific cross-sectional prevalence of high-risk HPV (%) clearly peaks before the age-specific incidence rate
of cervical cancer.
Bosch FX et al. J Clin Pathol 2002; 55: 24465.
Diagnosis
Cervical cytology - 1
The methodology is recommended by the European guidelines for quality
assurance in cervical cancer screening
1. A sample of cells is taken from the transformation zone of the cervix extended-tip wooden spatula(a) , endocervical brush (b), cervical broom (c)
c
http://www.eurocytology.eu/static/eurocytology/Quality%20Assurance2.pdf
2. Smeared into a glass slide
Cervical cytology - 2
a
b
3. Immediately fixed with fixative from a
dropper bottle (1) or by spraying (2)
c
http://www.eurocytology.eu/static/eurocytology/Quality%20Assurance2.pdf
1
2
Liquid-based cervical cytology
•
•
•
•
a plastic spatula with either an endocervical brush or a
cervical broom;
the sample is rinsed into a vial containing preservative
solution;
centrifuged to produce a cell pellet OR drawn through a
filter under negative pressure to collect cells;
the resulting cell sample is fixed onto a glass slide and
stained for examination under a microscope.
Advantages
•
•
•
There are fewer unsatisfactory specimens.
Each specimen requires a shorter interpretation time,
leading to increased efficiency and cost-effectiveness.
The material collected can also be tested for HPV DNA.
Results interpretation - 1
• Normal cytology - No abnormal cells are observed on the surface of their cervix upon
cytology.
• Cervical Intraepithelial Neoplasia (CIN) / Squamous Intraepithelial Lesions (SIL) precancerous lesions or the abnormal growth of squamous cells observed in the cervix.
SIL - cervical cytological screening or Pap smear testing.
CIN - histological diagnosis - biopsy or surgical excision.
• Low-grade cervical lesions (CIN-1/ LSIL) - early changes in size, shape, and number of
abnormal cells formed on the surface of the cervix
• High-grade cervical lesions (CIN-2;CIN-3/ CIS/ HSIL) - a large number of precancerous
cells on the surface of the cervix that are distinctly different from normal cells. They
have the potential to become cancerous cells and invade deeper tissues of the cervix.
Results interpretation - 2
• Carcinoma in situ (CIS) - Cancerous cells are confined to the cervix and have not
spread to other parts of the body.
• Invasive cervical cancer (ICC) / Cervical cancer - If the high-grade precancerous cells
invade deeper tissues of the cervix or to other tissues or organs, then the disease is
called invasive cervical cancer or cervical cancer.
o Invasive squamous cell carcinoma - Invasive carcinoma composed of cells
resembling those of squamous epithelium.
o Adenocarcinoma - Invasive tumour with glandular and squamous elements
intermingled.
▲ The key events that occur in high-grade squamous intraepithelial neoplasia (HSIL) and cancer. HPV Disease, Merck&Co. Inc., 2006
Results interpretation - 3
It is very important to clearly explain the result of a cytological test because women must
understand their risk and the importance of their future actions regarding correct
treatment options!
There are different classification systems and this table can be used for converting the
results.
Conversion table for different cytological classification systems
Papanicolaou
I
II
WHO
CIN
TBS 1991
TBS 2001
III
Atypical
glandular
cells
Atypical
Normal
Mild dysplasia
Condyloma
Infection,
reactive
repair
Negative for epithelial
abnormality
ASCUS
ASC-US
AGUS
Atypical
ASC-H glandular
cells
CIN I
IV
Moderate Severe
dysplasia dysplasia
CIN II
LSIL
HSIL
LSIL
HSIL
CIN III
CIS
V
AIS
CGIN
Invasive
AGUS carcinoma
AIS
ADAPTED AFTER http://www.eurocytology.eu/Static/EUROCYTOLOGY/Quality%20Assurance3.pdf
Colposcopy
• colposcope - magnifies the cervix
• allows the clinician to check carefully for abnormalities.
• when an abnormality is found, a biopsy (tissue sample) is taken.
Colposcopy with acetic acid washcolposcopic image suggestive of high grade
lesion
http://ircon.ro/pdf/Study- CERVUGID-Ovoules
HPV- DNA testing
Currently the most widely
used HPV testing methods
are based on the detection
of HPV DNA and include:
• polymerase chain reaction
(PCR)-based methods
• nucleic acid hybridization
assays
with
signal
amplification.
Polymerase Chain Reaction (PCR)
This is a molecular technique used
to amplify a specific region of a
DNA strand (the DNA target).
It consists of a series of 30-40
repeated temperature changes,
called cycles, with 3 steps in each
cycle.
Subsequent to PCR, analysis of the
amplified products and distinction
of HPV types can be achieved by
sequencing or hybridization with
type-specific
oligonucleotide
probes, using various methods.
3 steps of PCR
1.denaturation (the DNA strands separate to
form single strands)
2. annealing, one primer binds to one DNA
strand and another binds to the complementary
strand. The annealing sites of the primers are
chosen so that they will prime DNA synthesis in
the region of interest during extension
3. extension: The DNA polymerase synthesises a
complementary strand. The enzyme reads the
opposing strand sequence and extends the
primers by adding nucleotides in the order in
which they can pair.
Nucleic acid hybridization assays
with signal amplification
A group of qualitative or semi-quantitative multiplex assays in
which the DNA of the targeted HPV types is detected using
mixtures of probes (probe cocktails) for several HPV types
with similar clinical characteristics. None of the assays from
this group allow the exact determination of HPV type(s)
present in a clinical specimen, but show the results of the
tested group of HPV types as positive or negative.
HPV genotyping tests
After PCR amplification,
distinction of HPV types is
achieved by reverse hybridization
with type-specific probes using a
variety of formats.
With type-specific PCR, primers
are chosen that will only amplify
a single HPV genotype.
Sensitivity and specificity
Test accuracy refers to:
Sensitivity – proportion of
truly ill people in the
screened population who are
identified as ill by the
screening test
Specificity – proportion of
truly healthy people who are
so identified by the screening
test
Tests for CC screening
As far as today there is sufficient evidence that screening for cancer precursors
every 3-5 years between the ages 35 and 64 years by conventional cytology in a
high-quality programme reduces the incidence of invasive cancer by 80% or
more among the women screened. HPV molecular tests are very sensitive, but
they do not discriminate between transient and persistent infection and this
means less specificity.
HPV test was accepted for the triage of equivocal cytology (ASCUS) and follow
up of treated lesions.
New strategies can simplify the screening process or reduce the cost of
screening.
Recently, many wide, randomized clinical trials show that carcinogenic HPV DNA
screening is more sensitive than cytological screening for detecting histological
CIN3. A negative HPV test provides long-term risk stratification; this high
negative predictive value permits safe and cost-effective lengthening of the
cervical screening interval when HPV testing is used.
IARC Handbooks on Cancer Prevention 2005; www.ecca.info; Ronco G et al. Lancet Oncol. 2010; Mayrand MH et al. N Engl J Med. 2007; Bulk
S et al. Int J Cancer. 2007; Naucler P et al. N Engl J Med. 2007; Sankaranarayanan R et al. N Engl J Med. 2009; Bulkmans NW et al. Lancet.
2007; Khan MJ et al. J Natl Cancer Inst. 2005; Dillner J et al. BMJ. 2008.
Screening algorithms: new perspective
• The rationale for the change
is to invert the current
algorithm
Pap
Test>Colposcopy-HPV test, first
running the most sensitive
test (HPV test) and then the
most specific test (Pap test).
• HPV Vaccination
will
request further adjustments
in screening algorithm in the
next future.
Population based
oncological screening
Definition of oncological screening
“Screening” is an organized, controlled, systematic, public
health intervention actively and periodically proposed,
that involves the application of a relatively simple,
innocuous, acceptable, ripetible, and relative cheap (for
the organization, free for the involved population) test, to
an asymptomatic and well defined population, to obtain
detection of cancer at an earlier stage or of a precancerous lesion, with the goal to decrease the mortality
and, if possible, the incidence of the tumor, with an
effective and conservative treatment, possibly less
aggressive than in clinically detected cases.
Definition of population based screening
A screening programme with individual
identification and personal invitation of the
elegible population. An optimal program is a
screening program with quality assured at every
step in the process: identification and personal
invitation of the target population, performance
of the test, compliance, call/recall system,
second level diagnosis and treatment of the
lesions
detected,
data
registration,
communication and training.
von Karsa et al., 2008, Antilla et al., 2009
Cervical cancer screening
Among all malignant tumours, cervical cancer is
the one that can be most effectively controlled by
screening. Detection of cytological abnormalities
by microscopic examination of Pap smears, and
subsequent treatment of women with high-grade
cytological abnormalities avoids development of
cancer.
Miller, 1993
Impact
• If an optimal CCS policy is implemented in their
countries, with adequate funds and supports, the
figures of cervical cancer cases and deaths could
substantially decrease.
• As far as today many European countries have
developed population-based screening programs for
cervical cancers, although they differ greatly in terms of
organizational characteristics, implementation stage,
coverage and quality assurance.
von Karsa et al., 2008, Antilla et al., 2009
Finland
• In Finland organised cervical screening was introduced in the early
1960s; from the early 1970s the screening invitational coverage has
been almost complete.
• During 1955–1964 the incidence of invasive cervical cancer in Finland
was at a level of 15 cases per 100,000 woman-years age-adjusted to
the world standard population; currently the age-adjusted rate is 4
cases per 100,000 woman-years.
• The age-standardized mortality rates decreased over 80% from the
level of 7.0 deaths per 100,000 in early 1960s to 1.2 deaths per
100,000 in the 1990’s (rates adjusted for age to the world standard
population).
Hristova & Hakama, 1997; Anttila & Laara,2000
Cervical cancer incidence and mortality rates in Finland
Anttila A , Niemininen P, Cervical Cancer Screening Programme in Finland with an Example on Implementing Alternative Screening Methods. Coll. Antropol. 31 (2007) Suppl. 2: 17–22
UK
Cytological screening was introduced in the 1960s,
but an organised programme including a call/recall
system and quality assurance was not initiated
until1988. In the preceding years, mortality and
incidence decreased by 1-2% per year, whereas
since 1988 the decrease has been about 7% per
year, despite an increased underlying risk of disease
inwomen born since 1940
Sasieni et al., 1995; Quinn et al., 1999; Sasieni & Adams, 1999; Peto et al., 2004; Bray et al., 2005; IARC, 2005
Effect of screening on incidence of cervical cancer in England
Quinn M , Babb P, Jones J et al. Effect of screening on incidence of and mortality from cervical cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ
1999;318:904–908.
Strategy
The strategy of a screening programme must
clearly establish:
• Who is the target population
o general population
o certain age groups / gender categories
o certain geographic regions
o those with a certain risk level
• What detection tests shall be used, in what order and at what intervals they
shall be applied
• Who shall apply the tests and where they shall be carried out
• A screening programme must have a quality assurance structure
Hard to reach population
Important problems are associated with conducting the screening on hard-toreach population.
Definition of Hard to reach population (HTRP): those sections of the community
that are difficult to involve in public participation.
The term can be used to refer to minority group such as ethnic group, sometimes
to hidden populations such as illegal immigrants, sometimes to unserved groups
(no services available for these groups) or service “resistants” (people failing to
access the services that are available).
• no homogeneity in the term
• certain groups may be hard to reach in some contexts or locations and not in
others
• the term can bring some prejudices about the people “hard to reach”
• paradoxically top business women, can be “hard to reach” for cervical cancer
screening, because of lack of time
Prevention of infection: vaccination
Prevention of infection: vaccination - 1
Prevention activities aimed at reducing the incidence or
spreading of disease, or at least minimizing the
consequences of disease or health disorders
There are three levels of prevention:
•Primary prevention – the aim is to prevent disease –
as an example is vaccination or provizion of drinking
water..
•Secondary prevention – a number of measures to
allow early detection and rapid intervention – ex.
screening cervical cancer
•Tertiary prevention – reduces the number of
complications and consequences of diseases and
disorders of health - it increases the chance of
extending life expectancy – ex. in oncology, follow-up of
patients after therapy with the aim of early detection
of relapse of disease.
Prevention of infection: vaccination - 2
The vaccination protects a person
from future infection by the HPV highrisk types that can lead to cancer.
It is not a vaccine against cancer itself.
A person receives a series of three
shots over a 6-month period. Health
professionals inject these virus-like
particles (VLPs) into muscle tissue.
These particles induce a strong immune response, vaccinated persons create specific
antibodies that can detect, bind and neutralize the L1 protein on the surface of HPV.
Both available vaccines Gardasil/Silgard (quadrivalent – types 6, 11, 16 and 18) and
Cervarix (bivalent – types 16 and 18) demonstrate also a certain degree of crossprotection towards HPV types genetically and antigenically related to those included in
the vaccines, as follows: HPV 31, 33, 52, 58 similar with HPV 16; HPV 39, 45, 59 similar
with HPV 18.
VLPs
Preventive vaccines are based
on virus-like particles (VLPs).
The virus-like particles in the HPV
vaccine (similar to the real
human papillomavirus) have the
same outer L1 protein coat, but
they have no genetic material
inside, so they are non-infective.
VLPs enable the vaccine to induce a strong protective immune response.
If an exposure occurs, the vaccinated person's antibodies against the L1
protein coat covers the virus and prevents from releasing its genetic material.
Comparision of the commercial HPV vaccines (data 12/2011)
Gardasil/Silgard
Manufacturer
VLPs included
Cervarix
Adjuvant:
Produced in:
Merck/MSD
HPV 6- 20 g
HPV11- 40 g
HPV16- 40 g
HPV18- 20 g
Aluminium
Saccharomyces cerevisiae
Injection schedule
0,2,6 months
Indication
9-45 year women,
9-15 year men
10-25 year women
0,5 ml/i.m.
HPV 31
70-73% CC
90% genital warts
0,5 ml/i.m.
HPV 31, 33, 45
70-82% CC
Vol./aplication
Cross immunity
Effectiveness
GlaxoSmithKline
HPV16- 20 g
HPV18- 20 g
ASO4
Spodoptera frugiperda S19
Trichopusia ni Hi 5
0,1,6 months
Advantages and limits of CC vaccination
• It has been proven high efficacy of both vaccines in prevention premalignant cervical
lesions and cervical cancer (up to 70-82% of cases of cervical cancer)
• They have no therapeutic effect
• Vaccination prevents reinfection by vaccinal types but it cannot prevent already
present persistent infection
• There are also other types of cancer attributable to HPV (anal, vulvar, vaginal, penile,
oral, laryngeal, tonsilar)
• Silgard/Gardasil also prevent condyloma acuminata
• Vaccines have good safety profile ; the most common adverse reactions are fever
and site reactions – pain, redness, swelling
• Vaccines reduce the costs related to the diagnosis and treatment of precancerous
lesions and cervical cancer
Screening
vaccination
• Vaccination does not replace CC screening
• When girls vaccinated will reach the age of CC,
screening, different screening strategies will
be implemented (years of interval, algorithm).
• The exchange of information (list of
vaccinated women) between screening
centers and vaccination centers is mandatory.
Recommendation of WHO
Routine vaccination against HPV included in national
immunization programmes provided that:
1) the prevention of cervical cancer or other HPV related diseases
constitutes a public health priority
2) introduction of the vaccine is feasible
Target population:
girls aged 12-14 years – before initiation sexual activity
Expected results:
within 10 years there would be a reduction in the number women
conization for cervical precancerosis; positive effect in reduction
incidence of CC can be expected in longer term (15-25 years)
(wer, No 25, 2010, 237-243)
Diagnosis and treatment
of cervical pre-cancer lesions and cancer
disease
Abnormal Pap smear
Process step by step
Information and counselling
Endometrial biopsy
Treatment
Benign endometrial cells
Repeat Pap smear in 12 months
Repeat Pap smear in 12 months
Colposcopy
ASCUS (Atypical Squamous Cells of Undetermined Significance)
Treatment
High risk HPV DNA
Colposcopy
AGUS (Atypical Glandular Cells of Undetermined Significance)
LSIL (Low-grade Squamous Intraepithelial Lesion)
Repeat Pap smear after 6 and 12
months
Colposcopy
HSIL (High-grade Squamous Intraepithelial
Lesion)
Malignant Cells
Treatment
Colposcopy + Biopsy
Treatment
Treatment
See staging in cervical cancer
(Adapted after “ European guidelines for quality assurance in cervical cancer screening – Second edition”. Luxembourg: Office for Official Publications of the European Communities, 2008.
International Agency for Research on Cancer.)
TNM and FIGO staging 1
Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. May 2009;105(2):107-8. [
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. May 2009;105(2):103-4.
[NCCN Clinical Practice Guidelines in Oncology: Melanoma. V 1. 2011;Accessed March 28, 2011. Available at
http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.
TNM and FIGO staging 2
Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. May 2009;105(2):107-8. [
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. May 2009;105(2):103-4.
[NCCN Clinical Practice Guidelines in Oncology: Melanoma. V 1. 2011;Accessed March 28, 2011. Available at
http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
.
Staging, therapeutic approach and prognosis in cervical cancer
FIGO
Therapeutic approach
The 5-year survival rates
See screening algorithm
See screening algorithm
0
1. LEEP 2. Laser therapy 3. Conization 4. Cryotherapy 5.
Total abdominal or vaginal hysterectomy for
postreproductive patients
6. Internal radiation
therapy for medically inoperable patients
I
Conization, hysterectomy and possible chemoradiation
II
Hysterectomy or primary chemoradiation
III
Chemoradiation
IV
80 to 90%
60 to 75%
30 to 40%
Chemoradiation and possible Hysterectomy
0 to 15%
ADAPTED AFTER http://www.uicc.org/programmes/hpv-and-cervical-cancer-curriculum
Cryotherapy
• eliminates precancerous areas on the cervix by freezing them.
• about 15 ’ ;can be performed on an outpatient basis; only some
cramping or mild pain; can be done without anesthesia.
• for the treatment of small lesions; for larger lesions the cure rate is
below 80%.
Loop electrosurgical excision procedure (LEEP)
• removal of abnormal areas from the cervix using a thin heated wire, also
called large loop excision of the transformation zone (LLETZ)
• it can be performed under local anaesthesia on an outpatient basis
• it is successful in eradicating precancer in more than 90% of cases
• double purpose: treats the lesion and produces a specimen for
pathological examination
Hysterectomy
Hysterectomy = the uterus is surgically
removed with or without other organs
or tissues
http://www.cancer.umn.edu/cancerinfo/NCI/CDR62961.html
Radiation therapy
• Uses high-energy x-rays – kills cancer cells or keeps them from growing
• Two types of radiation therapy:
o External radiation therapy - a machine outside the body sends radiation
toward the cancer.
o Internal radiation therapy - a radioactive substance in needles, seeds, wires,
or catheters that are placed directly into or near the cancer.
Chemotherapy
• Uses drugs to stop the growth of cancer cells, either by killing the cells or by
stopping them from dividing.
• Taken by mouth or injected into a vein or muscle - enters the bloodstream,
reaches cancer cells throughout the body (systemic chemotherapy).
• Placed directly into the cerebrospinal fluid, an organ, or a body cavity such as
the abdomen, mainly affects cancer cells in those areas (regional
chemotherapy).
Resources
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World Health Organization (http://www.who.int/reproductivehealth/topics/cancers/en/index.html)
Union for International Cancer Control (http://www.uicc.org/programmes/hpv-and-cervical-cancer-curriculum)
Merck manual (http://www.merckmanuals.com/professional/gynecology_and_obstetrics/gynecologic_tumors/cervical_cancer.html)
Center for Disease Control and Prevention (http://www.cdc.gov/cancer/cervical/)
National Cancer Institute (http://cancer.gov/cancertopics/types/cervical)
European guidelines for quality assurance in cervical cancer screening; Second Edition; International Agency for Research on Cancer
Cancer Research UK (http://cancerhelp.cancerresearchuk.org/type/cervical-cancer/)
RHO/PATH (http://www.rho.org/)
American Cancer Society (http://www.cancer.org/cancer/cervicalcancer/index)
Alliance for Cervical Cancer Prevention (http://www.alliance-cxca.org/ )
Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2009. Atlanta: U.S. Department of Health and Human
Services; 2010.
Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR 2010;59; 69
WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in Europe.
Summary Report 2010. Available at www. who. int/ hpvcentre
Human papillomavirus vaccines - WHO position paper , Weekly epidemiological record, WHO, 10 APRIL 2009, No. 15, 2009, 84, 118–131,
(http://www.who.int/wer)
WHO HPV LabNet Newsletter No.8, 18 July 2011
Shepherd JP, Frampton GK, Harris P, Interventions for encouraging sexual behaviours intended to prevent cervical cancer, Cochrane Database
Syst Rev. 2011 Apr 13;(4):CD001035.
Weinstein LC, Buchanan EM, Hillson C, Chambers CV, Screening and prevention: cervical cancer, Prim Care. 2009 Sep;36(3):559-74.
Kasap B, Yetimalar H, Keklik A, Yildiz A, Cukurova K, Soylu F., Prevalence and risk factors for human papillomavirus DNA in cervical cytology, Eur
J Obstet Gynecol Reprod Biol. 2011 Nov;159(1):168-71.
Gonzalez-Bosquet E, Selva L, Sabria J, Pallares L, Almeida L, Muñoz-Almagro C, Lailla JM, Predictive factors for the detection of CIN II-III in the
follow-up of women with CIN I, Eur J Gynaecol Oncol. 2010;31(4):369-71.