Departement of

Anatomical Pathology
Praktikum
Patologi
Anatomi
Modul
Repoduksi
Pap smear dan Biopsi

dr. Susilorini
Departement of Anatomical Pathology
Medical Faculty of Sultan Agung Islamic
University
 Risk factors and causes of
cervical cancer
 Doctors cannot always explain why one woman develops
cervical cancer and another does not. However, we do
know that a woman with certain risk factors may be more
likely than others to develop cervical cancer. A risk factor is
something that may increase the chance of developing a
disease.
 Women who think they may be at risk for cancer of the
cervix should discuss this concern with their doctor. They
may want to ask about a schedule for checkups. If a
woman has an HPV infection, her doctor can discuss ways
to avoid infecting other people.
 The Pap test can detect cell changes in the cervix caused
by HPV. Treatment of these cell changes can prevent
cervical cancer. There are several treatment methods,
including freezing or burning the infected tissue.
Sometimes medicine also helps
 Studies have found a number of factors that may increase
the risk of cervical cancer. These factors may act together
to increase the risk even more:

 Human papillomaviruses (HPVs): HPV infection is the main risk

factor for cervical cancer. HPV is a group of viruses that can infect
the cervix. HPV infections are very common. These viruses can be
passed from person to person through sexual contact. Most adults
have been infected with HPV at some time in their lives. Some
types of HPV can cause changes to cells in the cervix. These
changes can lead to genital warts, cancer, and other problems.
Doctors may check for HPV even if there are no warts or other
symptoms.
 Lack of regular Pap tests: Cervical cancer is more common
among women who do not have regular Pap tests. The Pap test
helps doctors find precancerous cells. Treating precancerous
cervical changes often prevents cancer.
 Weakened immune system (the body's natural defense
system): Women with HIV (the virus that causes AIDS) infection or
who take drugs that suppress the immune system have a higher-
than-average risk of developing cervical cancer. For these women,
doctors suggest regular screening for cervical cancer.
 Age: Cancer of the cervix occurs most often in women over the
age of 40.
 Sexual history: Women who have had many sexual partners
have a higher-than-average risk of developing cervical cancer.
Also, a woman who has had sexual intercourse with a man who
has had many sexual partners may be at higher risk of developing
cervical cancer. In both cases, the risk of developing cervical
cancer is higher because these women have a higher-than-
average risk of HPV infection.
 Smoking cigarettes: Women with an HPV infection who smoke
cigarettes have a higher risk of cervical cancer than women with
HPV infection who do not smoke.
 Using birth control pills for a long time: Using birth control
pills for a long time (5 or more years) may increase the risk of
cervical cancer among women with HPV infection.
 Having many children: Studies suggest that giving birth to
many children may increase the risk of cervical cancer among
women with HPV infection.
 Diethylstilbestrol (DES) may increase the risk of a rare form of
cervical cancer and certain other cancers of the reproductive
system in daughters exposed to this drug before birth. DES was
given to some pregnant women in the United States between
about 1940 and 1971. (It is no longer given to pregnant women.)
Symptoms of cervical cancer

 Precancerous changes and early cancers of the cervix generally do

not cause pain or other symptoms. It is important not to wait to
feel pain before seeing a doctor.
 When the disease gets worse, women may notice one or more of
these symptoms:
 Abnormal vaginal bleeding
 Bleeding that occurs between regular menstrual periods
 Bleeding after sexual intercourse, douching, or a pelvic exam
 Menstrual periods that last longer and are heavier than before
 Bleeding after menopause
 Increased vaginal discharge
 Pelvic pain
 Pain during sexual intercourse
 Infections or other health problems may also cause these
symptoms. Only a doctor can tell for sure. A woman with any of
these symptoms should tell her doctor so that problems can be
diagnosed and treated as early as possible.
 In gynecology, the Papanikolaou test or
Papanicolaou test (also called Pap smear, Pap test,
cervical smear, or smear test) is a medical screening
method, invented independently by Aurel Babeş[1]
and Georgios Papanikolaou.
 Primarily designed to detect premalignant and
malignant processes in the ectocervix. It may also
detect infections and abnormalities in the endocervix
and endometrium.
 The test aims to detect and prevent the
progression of HPV-induced cervical cancer
and other abnormalities in the female genital
tract by sampling cells from the outer opening
of the cervix (Latin for "neck") of the uterus
and the endocervix.
 The endocervix may be partially sampled with the
device used to obtain the ectocervical sample, but due
to the anatomy of this area, consistent and reliable
sampling cannot be guaranteed. As abnormal
endocervical cells may be sampled, those examining
them are taught to recognize them.
 The endometrium is not directly sampled with the
device used to sample the ectocervix. Cells may
exfoliate onto the cervix and be collected from there,
so as with endocervical cells, abnormal cells can be
recognised if present but the Pap Test should not be
used as a screening tool for endometrial malignancy.
 It is generally recommended that females who have
had sex seek regular Pap smear testing. Guidelines on
frequency vary, from annually to every five years. If
results are abnormal, and depending on the nature of
the abnormality, the test may need to be repeated in
three to twelve months.
 If the abnormality requires closer scrutiny, the
patient may be referred for detailed inspection of the
cervix by colposcopy. The patient may also be
referred for HPV DNA testing, which can serve as an
adjunct to Pap testing
Diagnosis of cervical
cancer
 If a woman has a symptom or Pap test results that
suggest precancerous cells or cancer of the cervix, her
doctor will suggest other procedures to make a
diagnosis.
 These may include:
 Colposcopy: The doctor uses a colposcope to look at
the cervix. The colposcope combines a bright light with
a magnifying lens to make tissue easier to see. It is not
inserted into the vagina. A colposcopy is usually done in
the doctor's office or clinic.
 Biopsy: The doctor removes tissue to look for
precancerous cells or cancer cells. Most women have
their biopsy in the doctor's office with local anesthesia.
 • Punch biopsy: The doctor uses a sharp, hollow device to
pinch off small samples of cervical tissue.
• LEEP: The doctor uses an electric wire loop to slice off a
thin, round piece of tissue.
• Endocervical curettage: The doctor uses a curette (a
small, spoon-shaped instrument) to scrape a small
sample of tissue from the cervical canal. Some doctors
may use a thin, soft brush instead of a curette.
• Conization: The doctor removes a cone-shaped sample
of tissue. A conization, or cone biopsy, lets the
pathologist see if abnormal cells are in the tissue
beneath the surface of the cervix. The doctor may do
this test in the hospital under general anesthesia.
Conization also may be used to remove a precancerous
area.

A pathologist checks the tissue with

a microscope
 It is not a perfect test. "A nurse
performing 200 tests each year would
prevent a death once in 38 years.
During this time she or he would care for
over 152 women with abnormal results,
over 79 women would be referred for
investigation, over 53 would have
abnormal biopsy results, and over 17
would have persisting abnormalities for
more than two years.
At least one woman during the 38 years
would die from cervical cancer despite
being screened."[2]
 Slide Preparation
:
 The Traditional Method: the conventional method of
preparation for the laboratory is to spread the collected material
on a glass slide and to fix it immediately either by spraying the
slide or by immersing it in vial of preservative. To avoid air-drying
errors in the interpretation the slide should be fixed right away.
Sometimes the smears placed on the glass slide are thick and
difficult to analyze.
 The ThinPrep: the liquid-based system uses a proprietary fixative
into which the clinician places the collection devices. The devices
are agitated for a prescribed period, and the vial containing the
fixative is sealed, labeled, and forwarded to the laboratory where
the slide actually is prepared. The U.S. Food and Drug
Administration (FDA) allows the ThinPrep technique to be
marketed as better able to detect both low-grade and high-grade
squamous intraepithelial lesions (LSIL and HSIL, respectively) than
the conventional method of preparation (3).
 The SurePath System: it also uses a proprietary preservative
solution into which a supplied collection device is placed. The
liquid and the collection device are sent to the laboratory. The FDA
has approved this technique for use and allows it to be marketed
as equivalent to the conventional Pap test. Several other methods
of cell collection and preparation currently are in development.
 Methods of Collection

 In the recent past, adaptation in the collection and preparation

methods, new methods of interpretation, and the introduction
of adjunctive tests have been shown to improve the sensitivity
of the Pap test without markedly decreasing its specificity.
 Originally, cervical cells samples were obtained from the
posterior vaginal pool. It has been shown repeatedly that this
is a poor source of cells and that the sample should be
collected only from the portio and endocervix.
 Cervical cytology samples should be obtained using either a
spatula and endocervical brush or an instrument that can
collect cells from both the ectocervix and endocervix.
 Technical aspects
 Samples are collected from the outer
opening or os of the cervix using an
Aylesbury spatula and an endocervical
brush, or (more frequently with the advent
of liquid-based cytology) a plastic-fronded
broom. The broom is not as good a
collection device, since it is much less
effective at collecting endocervical
material as the spatula and brush.[3]
 The cells are placed on a glass slide and
checked for abnormalities in the laboratory
.
1.Micro anatomy of the uterine cervix: 1= Nulliparous, 2=
Multiparous (A: external os, pink area = non keratinized
squamous epithelium, purple area = glandular epithelium
composed of one layer of mucin secreting and ciliated
cells).
2. Micro anatomy of the uterine cervix: 1 = Nulliparous, 3
= Menopausal (A: External os, violet area = non-
keratinized squamous epithelium, purple area = glandular
epithelium composed of one layer of mucin secreting and
ciliated cells).
 Practical aspects

 The physician or operator collecting a sample for the test inserts a

speculum into the patient's vagina, to obtain a cell sample from the cervix.
 A pap smear appointment is normally not scheduled during menstruation.
 The procedure is usually painful, because of the neuroanatomy of the
cervix. However, this can depend on the patient's anatomy, the skill of the
practitioner, psychological factors, and other conditions. Results usually
take about 3 weeks.
 Slight bleeding, cramps, and other discomfort can occur afterwards.
 Other tests, including the TruTest, an endometrial biopsy used for early
detection of uterine cancer, can be performed during the same visit.
Smear sampling/slide preparation for conventional cytology
Smearing of the exocervical sample with a wooden spatula (Ayre's
spatula). Some may have a longer bifid extremity for a better
endocervical sampling
Smearing of the endocervical sample taken with the thinner

extremity of the wooden spatula.

Spray fixation: immediate, during a few seconds, with a spray/slide
distance around 20 cm.
 superficial cell, scanning electron
microscopy: flat cell with a small
nucleus (arrow).

superficial cell, scanning electron

microscopy: Flat cell with traces of other
cells and several Döderlein bacilli.

1Scanning electron
microscopy: superficial cells
and Döderlein bacilli
 The sample is stained using the
Papanicolaou technique, in which tinctorial
dyes and acids are selectively retained by
cells.
 Unstained cells can not be visualized with
light microscopy. The stains chosen by
Papanicolau were selected to highlight
cytoplasmic keratinization, which actually
has almost nothing to do with the nuclear
features used to make diagnoses now.
  Studies of the accuracy of
conventional cytology report:[4]
 sensitivity 72%

 specificity 94%
 Liquid based monolayer
cytology
 Since the mid-1990s, techniques
based around placing the sample into
a vial containing a liquid medium
which preserves the cells have been
increasingly used. The media are
primarily ethanol based.
 Two of the types are Sure-Path (
TriPath Imaging) and Thin-Prep (
Cytyc Corp).
Smear sampling/slide preparation
for liquid-based cytology  
 Once placed into the vial, the sample is
processed at the laboratory into a cell
thin-layer, stained, and examined by light
microscopy.
 The liquid sample has the advantage of
being suitable for low and high risk HPV
testing and reduced unsatisfactory
specimens from 4.1% to 2.6%.[5]
 Proper sample acquisition is crucial to the
accuracy of the test; clearly, a cell that is
not in the sample cannot be evaluated
 Studies of the accuracy of liquid
based monolayer cytology report:
 sensitivity 61%[6] to 66%[4]
 specificity 82%[6] to 91%[4]
Some[5], but not all studies[4][6], report increased sensitivity
from the liquid based smears
 Human papillomavirus
testing
 The presence of HPV indicates that
the person has been infected, the
majority of women who get infected
will successfully clear the infection
within 18 months. It is those who
have an infection of prolonged
duration with high risk types[7] (e.g.
types 16,18,31,45) that are more
likely to develop Cervical
Intraepithelial Neoplasia due to the
 Studies of the accuracy of HPV
testing report:
 sensitivity 88% to 91% (for
detecting CIN 3 or higher)[6] to 97%
(for detecting CIN2+)[8]
 specificity 73% to 79% (for detecting
CIN 3 or higher)[6] to 93% (for
detecting CIN 3 or higher)[8]
 By adding the more sensitive HPV Test, the specificity may
decline. However, the drop in specificity is not definite. [9]
 If the specificity does decline, this results in increased
numbers of false positive tests and many women who did
not have disease having colposcopy[10] and treatment.
 A worthwhile screening test requires a balance between the
sensitivity and specificity to ensure that those having a
disease are correctly identified as having it and equally
importantly those not identifying those without the disease
as having it. Due to the liquid based pap smears having a
false negative rate of 15-35%, the
American College of Obstetricians and Gynecologists[
citation needed] and
American Society for Colposcopy and Cervical Pathology
[11] have recommended the use of HPV testing in addition
to the pap smear in all women over the age of 30.
 Due to the liquid based pap smears
having a false negative rate of 15-
35%, the
American College of Obstetricians and Gy
G
[citation needed] and
American Society for Colposcopy and Ce
[11] have recommended the use of
HPV testing in addition to the pap
smear in all women over the age of
30.
 Regarding the role of HPV testing,
randomized controlled trials have
compared HPV to colposcopy.
 HPV testing appears as sensitive as
immediate colposcopy while reducing the
number of colposcopies needed.[12]
 Randomized controlled trial have
suggested that HPV testing could follow
abnormal cytology[6] or could precede
cervical cytology examination.[8]
 A study published in April 2007 suggested
the act of performing a Pap smear
produces an inflammatory cytokine
response, which may initiate immunologic
clearance of HPV, therefore reducing the
risk of cervical cancer.
 Women who had even a single Pap smear
in their history had a lower incidence of
cancer. "A statistically significant decline in
the HPV positivity rate correlated with the
lifetime number of Pap smears received."
[13]
 Automated analysis
 In the last decade there have been
successful attempts to develop automated,
computer image analysis systems for
screening.[14]
 Automation may improve sensitivity and
reduce unsatisfactory specimens.[15]
 One of these has been FDA approved and
functions in high volume reference
laboratories, with human oversight.[
citation needed]
 Automated Slide Interpretation:

 Because the interpretation of cervical cytology is

labor intensive, there has been great interest in
the development of computer-based systems that
can read cervical cytology accurately.
 The FocalPoint slide profiler has been approved
by the FDA for primary screening of cervical
cytology. This device identifies up to 25% of
slides as negative for CIN for which no human
review is required (4). Because computerized
interpretation may decrease turn-around time
and can potentially be cost saving, a number of
corporations are developing slide interpretation
products.
 Various Diagnostic
Terminologies:
 Traditional Nomenclature :Squamous
atypia, Condyloma, Mild dysplasia,
Moderate dysplasia, Severe dysplasia
 CIN Nomenclature: squamous atypia ,
Condyloma, CIN I, CIN II, CIN III,
Carcinoma-in-situ (CIS) carcinoma
invasive
 Bethesda System Nomenclature (SIL):
ASCUS. Low-grade SIL, High-grade SIL.
 The Bethesda 2001 Terminology
Committee suggested that whenever
a slide is prepared or interpreted
using any form of automation, that
fact should be mentioned in the
report that is returned to the
clinician
Matrix of Diagnostic Categories
 Cytology of Squamous
Epithelium
 During normal maturation, the squamous epithelium of the
uterine cervix can be conceptualized as differentiating from
basal/reserve cells to parabasal cells to intermediate cells to
superficial cells. These four cells are the keys to the most common
daily diagnostic problem in cytology. The cytoplasm provides
information about the origin and functional differentiation of a cell.
 For this reason, cytoplasmic features are used to determine the
degree of squamous differentiation. The cytoplasmic hallmarks of
squamous differentiation are distinct cell boundaries and the
accumulation of dense cytoplasm.
 The nucleus provides information about the health of the cell
(whether it is normal, inflamed, hyperplastic, or neoplastic).
 Nuclear features determine where in the continuum of neoplastic
transformation, or carcinogenesis, the cell may be. Changes in
nuclear size, configuration, and chromatin (hyperchromasia,
coarsening, and eventually irregular distribution) and the
appearance of visible nucleoli are the main nuclear features of
ensuing carcinogenesis.
 Inflammatory Changes and
Specific Infections
 Pruritis and vaginal discharge are among the
most common reasons that a woman seeks
medical advice from her gynecologist. Although
Pap smear can be useful in identifying specific
infectious agents, it should not be used in lieu of
more effective diagnostic tests. Many things can
cause inflammation; the mere presence of
inflammatory change on Pap smear is a poor
indicator of the presence of infection.
Inflammatory change can mimic dysplasia.
Patients with persistent inflammatory change are
at high-risk for a bonafide squamous abnormality
(cervical intraepithelial neoplasia/ squamous
intraepithelial lesion).
 Trichomonas Vaginalis: this is an oval
or pear-shaped organism that varies Leptothrix: it is mixed lactobacilli. The
from 8 to 30 micro m. The trichomonad
nucleus (thin, elliptical) must be organisms are long, thin (less than half as
identified to diagnose this infection. Red thick as Candida) and flexible. If leptothrix
granules in cytoplasm may be seen.
Slightly enlarged, dark nuclei and is present, Trichomonas is usually
perinuclear halos are common, present, but reverse is not true
mimicking low grade dysplasia
 Candida Species: it is associated with a
change in vaginal glycogen flora or pH.
For example: Pregnancy, late luteal phase
of cycle, diabetes mellitus,
immunosuppression, debilitating disease,
steroids, birth control pills, broad spectrum
antibiotics, chemotherapy are associated
with candida infection. Pseudohyphae
(sticks) and yeast (stones) are seen.

Actinomyces: it is associated with IUD use;

rarely is associated with other foreign objects
(tampons or pessaries). The patient may be
asymptomatic or have pelvic pain. Cytologic
findings are colonies of variably gram-positive,
long, thin, filamentous bacteria that are reddish,
branch are irregularly beaded, and radiate from
central area.
Herpes: it can be asymptomatic or present as
blisters, which can ulcerate and be painful. Herpes
simplex types I and II are morphologically
indistinguishable. The most characteristic cells are
multinucleated and the nuclei mold each other. The
nuclei are enlarged and the chromatin marginates,
resulting in a ground glass appearance. There may
be red nuclear inclusions. Late changes are
characteristic and diagnostic; early changes can
mimic CIN III. Patients with herpes infection are in
high-risk group for CIN/SIL.

Gardnerella vaginalis (Bacterial

Vaginosis): it is a gram-negative,
comma-shaped coccobacillus. The
bacteria tend to agglomerate onto
squamous cells (clue cells). Smears
usually show a characteristic granular
blue background of small coccobacilli,
but the background is otherwise clean,
often accompanied by slight
parakeratosis.
 Chlamydia trachomatis: it is an
obligate intracellular bacterium that is
associated with granular cytoplasmic
inclusions. It is the most common
cause of non-gonococcal urethritis/
cervicitis. It may cause 20 to 25% of
cases of pelvic inflammatory disease,
which can result in infertility and
ectopic pregnancy. Chlamydia
trachomatis is frequently
asymptomatic.

The value of Pap smear in

diagnosing Chlamydia is uncertain.
Fine vacuolization of metaplastic
cells (having a "moth eaten"
appearance) may correlate with
high risk of infection. Nebular
bodies though rare and difficult to
see, may be more specific.
Chlamydia changes can mimic low-
grade dysplasia.
 Differential Diagnosis of Dysplasia vs
Inflammatory Change:
 Inflamed nuclei are big, but not dark; or
dark, but not big. Red nuclei indicate
inflammation.
 Dysplastic nuclei are big and dark. Blue
nuclei indicate true dysplasia. Dysplasia vs
inflammation: matter of degree: more
pleomorphic, larger nuclei; more irregular
nuclear outline; more abnormal chromatin
crisp and distinct; more cellular disorder.
Halos: inflammatory vs kilocytotic (5).
 The Pap smear is only a screening test for
cervical cancer; it has a low, but significant
diagnostic error rate.
 A "negative" report does not guarantee the
absence of cervical cancer.
 Close surveillance of high-risk patients, including
those with multiple infections and heavy
inflammation, is important.
 All abnormal Pap smear results should be
followed up, and of great importance suspicious
lesions should be biopsied and suspicious
symptoms investigated, even when the Pap is
negative
 Cytology of the Glandular
Epithelium:
Endocervical cells are tall and columnar, and can be secretory or ciliated.
Endocervical cells can be seen singly or in strips or sheets. See pictures below:
Endometrial cells can also form three-dimensional clusters of glandular cells, without central stroma.
The cells are small and crowded, and the nuclei are usually degenerated and hyperchromatic can
mimic carcinoma in situ. A common everyday problem in Pap smear diagnosis is distinguishing
endometrial cells from endocervical cells. This can be important, since shedding of endometrial cells
is abnormal in the second half of the menstrual cycle (especially past 40 years of age) or any time in
postmenopausal women. Abnormal shedding of endometrial cells carries with it an increased risk of
endometrial hyperplasia or neoplasia. See picture below:
 Treatment of Cervical Lesions:
 What happens if my Pap smear is
abnormal?
 The current means of screening for
cervical cancer is the Pap smear. If your
Pap smear is abnormal the next step is
colposcopy. This procedure is performed
in the office. Your doctor will use a special
binocular instrument, a colposcope, to look
at your cervix.
Colposcopy results: biopsies of
the cervix
What is colposcopy?
Colposcopy is a gynecological procedure
that allows a physician to look directly
at the cervix with a microscope in order
to detect and examine abnormalities of
the cervix
 Why is colposcopy done?
 Colposcopy is done in one of two
circumstances: either when the result of a
Pap smear is abnormal or when the cervix
looks abnormal during the collection of a
Pap smear.
 Even if a Pap smear result is normal,
colposcopy is ordered when the cervix
appears visibly abnormal to the clinician
performing the Pap smear.
 The purpose of the colposcopy is to
determine what is causing the abnormal
looking cervix or the abnormal Pap smear
so that appropriate treatment can be
given.
 During colposcopy, special tests (acetic
acid wash, use of color filters, and
sampling (biopsy) of tissues from the
cervix) can be done.
 Colposcopy is not to be confused with
culdoscopy, which is the insertion of an
instrument through the wall of the vagina
in order to view the pelvic area behind the
vagina
 What are the most common
treatments for HSIL?

 If your doctor determines that you have a

cervical lesion that is of high enough
grade, they may advise you to have the
lesion removed. The two most popular
methods of removing cervical lesions are
by "LEEP" or "by Cold Knife Cone". Both of
these procedures are quick, fairly
unintrusive, and typically have a quick
recovery time.
What can the patient
expect after the surgical
procedure?
There may be some mild
crampy discomfort.
Discharge may be expected
post operation.
They should shower and
avoid tub baths.
Do not use tampons or
douche.
Do not have intercourse for
the alotted time suggested
by your doctor.
 Normal ectocervix

Structure of the ectocervix : details of

the superficial layers : superficial cells
(5 or 6 layers). The N/C ratio is very
low and the axis of cells is parallel to
the basement membrane

. Structure of the ectocervix - details

of basal, parabasal and intermediate
layers: connective tissue, basal cells
(one layer), parabasal cells (two
layers), intermediate cells (some
layers) with inter-cellular bridges.
The N/C ratio of basal and parabasal
cells is high.
 . immunofluorescence - antibody
against collagen IV - The epithelium has
a continuous basement membrane (x).
The basement membrane of the vessels
is also labelled (arrow).

. immunohistochemistry -
antipankeratin (KL1) antibody,
positivity of intermediate and
superficial cells. Basal and
PAS staining: intermediate and
parabasal cells are negative
superficial cells rich in glycogen
 Normal endocervix

epithelium composed of one layer of

epithelium composed of one layer of
mucin secreting cells with numerous
mucin secreting cells with few ciliated
reserve cells. Slight hyperplasia of the
cells (+).
reserve cells
 transmission electron microscopy, endocervical cells covered with
microvilli (green arrows) and with numerous secretory vacuoles (red
arrows

scanning electron microscopy, one ciliated cell with cilia (7

microns long)
. immunohistochemistry: the proliferative
immunohistochemistry with anti-
activity as visualised by anti-Mib1 . CD1A antibody shows occasional
antibody is limited to occasional basal
dendritic cells (circles).
and parabasal cells (circles)
 References
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