Download Case 690: Why do I need a Pap test..?

Case 690: Why do I need a Pap test..?
Authors and Affiliations
Dr Siti Noratikah,
University of Adelaide
Associate Professor Margaret Davy,
School of Paediatrics and Reproductive Health,
University of Adelaide
Associate Professor Paul Duggan,
School of Paediatrics and Reproductive Health,
University of Adelaide This case explores the principles of cervical cancer screening, and further
management of invasive cervical cancer
Case Overview
Learning Objectives
The graduating student should be able to†¦
describe
to a patient how a Pap smear is done
understand
appropriate follow up of an abnormal Pap smear
understand
the terms LSIL and HSIL
understand
the risk factors that predisposes to cervical abnormalities
understand
the pathophysiology of cervical cancer
understand
the appropriate management of invasive cervical cancer
Question 1 : FT
Question Information:
Sarah Smith is a 24-year old accountant and attends her local clinic for a routine health check-up. Her
doctor asks Sarah whether she is up to date with her Pap tests. Sarah has never had a Pap test as she
feels that she does not need one.
Sarah enjoys good health and did have asthma as a child but is no longer on any medication. She has
been sexually active since the age of 16. She has no known allergies and the only medication she is on
currently is the oral contraceptive pill. She is a non-smoker and drinks four to seven standard drinks in a
week. She is not aware of any significant family history.
The doctor stresses to Sarah that it is important for her to have a Pap test done every two years as part
of the screening programme for cervical cancer. Sarah asks the doctor to describe for her what the Pap
smear entails and how the procedure is performed.
Question:
Describe what should be explained to Sarah.
Choice 1: null Score : 0
Choice Feedback:
The Pap test is a test recommended to all women who have ever been sexually active. The smear can
detect changes in cells in the cervix before they become cancerous and allow simple treatment to
prevent cancer of the cervix from occurring. Most, but not all, cervical cancers occur in sexually active
women because a sexually transmitted virus called HPV brings about these cell changes.
In Australia, the lifetime risk of a woman developing cancer of the cervix is about 1% and was higher
before the introduction of the Pap smear screening program. Vaccination against HPV infection is
expected to reduce this risk even further, and if Sarah has not been vaccinated already this should be
considered.
Sarah has not had an internal examination before and the doctor will show her the speculum and
demonstrate with the speculum open how the brush or spatula will be used. Sarah will be reassured
that although this is probably an embarrassing examination it should not be uncomfortable and will take
about a minute to perform. Usually, the cells are spread thinly on a glass slide and sprayed to prevent
drying before being sent the laboratory.
Before asking Sarah to undress, some doctors may discuss the alternative of liquid-based cytology,
which in Australia, Sarah will have to pay extra for. Liquid based cytology may have a superior detection
rate than conventional cytology and is required in special circumstances (e.g. HPV typing in a woman
with a proven high grade squamous intraepithelial lesion).
After the smear has been taken the doctor will perform a gentle internal examination to assess the size
and position of the uterus and check that the ovaries are not enlarged.
Question 2 : FT
Question Information:
Sarah decides to have the Pap test. This is done and arrangements are made with her for further
follow-up. After two weeks, Sarah comes back to the practice, and is told by her doctor that the Pap test
results show Sarah has a low grade squamous intraepithelial lesion. This is often referred to as 'LSIL'.
Question:
Describe in lay terms what this means
Choice 1: null Score : 0
Choice Feedback:
LSIL refers to a minor abnormality detected in the squamous (skin) cells sampled from the cervix.
These are due to infection by HPV and In the majority of cases the woman will spontaneously clear this
abnormality without treatment.
In the absence of other risk factors simple surveillance is appropriate with a repeat smear in twelve
months. This is the case with Sarah. However, a small proportion of LSIL will progress to high-grade
abnormalities probably due to infection by a more aggressive type of HPV. Thus, it is important that
both the doctor and Sarah are aware that follow up is mandatory.
Question 3 : SC
Question Information:
The doctor describes to Sarah the significance of a low grade squamous intraepithelial lesion (LSIL).
Sarah understands that the condition is usually self-limiting, but some form of surveillance is required. A
plan of management must be defined.
Question:
Which one of the following is the most appropriate plan of management?
Choice 1: Repeat Pap test in 12 months Score : 1
Choice Feedback:
Correct. According to the NHMRC guidelines, another Pap test should be performed in 12 months to
monitor the progression/regression of the cervical abnormality. LSIL is a sign of HPV infection and the
majority of cases will regress spontaneously. The repeat Pap test in 12 months will be normal if the
infection has been cleared by the immune system. However, referral for colposcopy is recommended if
this is a first LSIL AND there is another risk factor present.
Risk factors include immunosuppression (e.g. HIV infection, renal transplant recipient), past history of a
high grade abnormality, age over 30 years (older women are less likely to clear the virus
spontaneously), or if there are abnormal symptoms such as postcoital bleeding.
Choice 2: Repeat Pap test in two years Score : 0
Choice Feedback:
Incorrect. Two-yearly Pap tests are a screening measure and this plan is only for those whose Pap test
results are consistently normal. As this is a first presentation of an abnormal smear, a Pap test should
be arranged eariler than this for follow-up.
Choice 3: Refer for colposcopy Score : 0
Choice Feedback:
Incorrect. This is a first presentation of an abnormal smear. Observation and follow-up with a second
Pap test in 12 months is more appropriate. 91% of low-grade abnormalities on Pap smear in young
women regress within 36 months as reported by Szarewski and Sasieni in The Lancet. (see Critique for
Reference list).
If Sarah was older (age more than 30), immunosuppressed, had a past history of high grade disease,
or had symptoms such as postcoital bleeding she should be referred directly for colposcopy at this time.
Choice 4: Refer for Large loop excision of transformation zone (LLETZ) Score : 0
Choice Feedback:
Incorrect. Large loop excision of transformation zone (LLETZ) is a treatment modality and is only
required if there is a persisting lesion.
Question 4 : MS
Question Information:
Sarah is worried about the results of the Pap test, and is particularly concerned about her risk of cancer.
After counselling Sarah regarding the excellent prognosis associated with early detection of LSIL and
the importance of follow up, Sarah agrees to return in 12 months time for another Pap smear. However,
she wants to know if there are any risk factors for cervical cancer, and if she could have avoided them.
Question:
Which of the following are risk factors for cervical cancer?
Choice 1: Human papillomavirus (HPV) infection Score : 1
Choice Feedback:
Correct. HPV infection is a risk factor for cervical cancer. Although HPV infections are also responsible
for genital warts, certain HPV strains, such as HPV 16 and HPV 18 are known as high risk strains as
infection with them can predispose to having cervical cancer. However, the majority of women who
have had an HPV infection do not develop cervical cancer.
Choice 2: Smoking Score : 1
Choice Feedback:
Correct. Smoking is another risk factor in cervical cancer. In a case-controlled study done in United
States, it was shown that women who smoke more than 40 cigarettes a day are at two-times excess
risk of developing invasive cervical cancer, even when corrected for pre-existing HPV infection.
Although the mechanism of this is still poorly understood, it is suspected that smoking causes immune
dysregulation which predisposes to cervical cancer.
Choice 3: Alcohol intake Score : -1
Choice Feedback:
Incorrect. There is no evidence linking alcohol intake and cervical cancer. Although studies have been
done to investigate alcohol consumption as an independent risk factor, they have all been negative so
far.
Choice 4: Family history of breast cancer Score : -1
Choice Feedback:
Incorrect. Family history of breast cancer is a risk factor for ovarian cancer, not cervical cancer.
Choice 5: Immunosuppresion Score : 1
Choice Feedback:
Correct. There is a nine-fold increased risk of cervical cancer in patients who are post-renal transplant.
Maiman and colleagues have also shown that HIV-positive women with cervical cancer had significantly
more extensive and multifocal lesions compared to HIV-negative women. (see References in Critique).
Choice 6: Chlamydia infection Score : 1
Choice Feedback:
Correct. Although most women may be asymptomatic with a Chlamydia infection, it confers two-times
increased risk of developing subsequent invasive cervical cancer.
Choice 7: Gonorrhoea infection Score : 0
Choice Feedback:
Incorrect. Although Gonorrhoea is a sexually transmitted disease and is thought to be implicated in the
progression of cervical cancer, no study has been done yet to fully explore this hypothesis.
Choice 8: Oral contraceptive pill (OCP) Score : 1
Choice Feedback:
Correct. In a systematic review of 28 studies looking at relationship between use of OCP and cervical
cancer, the relative risk of cervical cancer increases with longer use. For women who have been using
OCP for 10 years or more, the relative risk ranges between 2.2 to 2.5. (see Reference list in Critique).
This must be put in perspective. Squamous cell carcinoma of the cervix (and its precursor) is a readily
detectable disease and all patients prescribed an oral contraceptive pill should be in a Pap smear
surveillance program. The increased risk of cervical cancer must be balanced against the protective
effective of the oral contraceptive pill against cancers such as carcinoma of the ovary - a disease that is
not readily detectable and for which there is no easy form of surveillance or screening.
Choice 9: Family history of cervical cancer Score : -1
Choice Feedback:
Incorrect. Current studies have yet to find a genetic and hereditary component to cervical cancer.
Question 5 : SC
Question Information:
Twelve months later Sarah has another Pap test. The results come back as being positive for highgrade squamous intraepithelial lesion (HSIL).
Question:
Which one of the following is the most appropriate next step in management?
Choice 1: Repeat Pap test in 12 months Score : -1
Choice Feedback:
Incorrect. The fact that the Pap test shows HSIL indicates that a colposcopy is required to assess the
lesion as it is now a pre-malignant lesion.
Choice 2: Repeat Pap test in two years Score : 0
Choice Feedback:
Incorrect and arguably negligent. Two-yearly Pap tests are only for those whose results are consistently
normal. This abnormal Pap test needs to have a more detailed follow-up and investigation done - which
will initially involve a colposcopy.
Choice 3: Refer for colposcopy Score : 1
Choice Feedback:
Correct. A colposcopic assessment is required in any women whose Pap test shows changes
suggestive of HSIL. This diagnosis is likely to be confirmed by colposcopically directed biopsy and
require local treatment (usually LLETZ, although some units prefer laser excision or ablation).
Furthermore, there is 0-3% chance of having an invasive cancer at the time of first presentation with
HSIL on a Pap test.
Choice 4: Refer for LLETZ Score : 0
Choice Feedback:
Incorrect. A colposcopy and directed (punch) biopsy should be done first, because occasionally there is
no confirmed HSIL and then LLETZ is over-treatment. There may be some special circumstances
where "see and treat" (i.e. proceeding straight to LLETZ) is justified but that is not recommended as
routine practice.
Question 6 : MS
Question Information:
A referral is arranged for Sarah to have a gynaecological opinion. Three weeks later, Sarah is seen and
colposcopy is performed. There is no macroscopic abnormality but staining with acetic acid shows a
small area of aceto-white change with associated small vessel changes of mosaicism and punctation. A
targeted biopsy of this lesion is performed and sent off to histopathology. It is noted that the
squamocolumnar junction is entirely visible. Result of the pathology confirms that it is a high-grade
squamous intraepithelial lesion.
Sarah is counselled about this and advised to undergo treatment. There are various treatment options:
Laser
ablation
Laser
excision of the transformation zone
Radical
Large
diathermy
loop excision of the transformation zone (LLETZ)
The most widely used is LLETZ as this is simple, relatively cheap and provides tissue for histological
analysis. Cryotherapy is inadequate due to insufficient depth of destruction with that method.
Question:
What further follow up is required?
Choice 1: Colposcopy at six months Score : 1
Choice Feedback:
Correct. NHMRC guidelines recommend that repeat cervical cytology and colposcopy be performed at
4-6 months as this can identify if there has been treatment failure sooner than cytology alone.
Choice 2: HPV typing at 12 months Score : 1
Choice Feedback:
Correct. HPV typing is a sensitive and specific test which is used to predict women who are at high risk
for recurrence (with a 98-100% negative predictive value). At 12 months, women who have been
treated should undergo repeat cervical cytology and HPV typing, which is repeated at 24 months. This
is called HPV †˜ test for cure†™.
If consecutive tests are negative the woman may go back to screening as per general population (i.e.
two yearly). If there is persisting high risk virus present the woman is recommended to have annual Pap
tests indefinitely and to have repeat colposcopy if LSIL or HSIL is detected.
Choice 3: Repeat Pap test in 2 years. Score : -1
Choice Feedback:
Incorrect. Recurrence rate increase steeply in the first 6-12 months post-treatment and may be the
result of further progression of the disease or inadequate treatment. This is why women who have been
treated with HSIL should be under continued surveillance.
Choice 4: Six monthly Pap tests until two consecutive clear smears Score : -1
Choice Feedback:
Incorrect. Guidelines are for a colposcopy and smear at 4-6 months post treatment of HSIL followed by
annual cytology and HPV typing until the woman has tested negative on two consecutive occasions.
Question 7 : MS
Question Information:
Mary, Sarah†™s sister, has also never had a Pap smear. She is 29 years old and is otherwise fit and
healthy.
For the last 6 months however, she has noticed some vaginal bleeding post-coitus which she thought
would resolve by itself. Her menses are regular and she has no spotting in between cycles. She
smokes 20 cigarettes/day since she was 16. She has no children. Feeling concerned about what has
happened to Sarah and the †˜ unresolved bleeding†™, Mary sees her local GP who examines her
after taking a detailed history.
On observation of the cervix, there is an area which is friable and bleeds to touch. A Pap smear is
performed but the doctor informs Mary that an assessment of the cervix by colposcopy is needed.
Arrangement for follow-up is made with Mary.
Two weeks later, Mary is seen by a gynaecologist. Her Pap smear results show she has HSIL with
features suggestive of invasive disease. This is discussed with her and as she is symptomatic,
colposcopy and biopsy is done. Result of the biopsy confirms that it is an invasive cervical cancer.
Question:
Which of the following investigations should be done?
Choice 1: Full blood count, urea, creatinine, electrolytes, liver function test Score : 1
Choice Feedback:
Correct. It is important to establish a baseline of renal and hepatic function.
Choice 2: Chest X-ray Score : 1
Choice Feedback:
Correct. Although spread of cervical cancer is more regional than distant, it is possible for metastases
to be found in the lung and if so, this would be the most advanced stage of the disease.
Choice 3: Pelvic examination under anaesthesia with cystoscopy and proctoscopy Score : 1
Choice Feedback:
Correct. Staging of cervical cancer is based on clinical findings and pelvic examination under
anaesthesia and is used alongside cystoscopy and proctoscopy to see if there are any extension of the
disease.
Choice 4: CT pelvis and abdomen Score : 1
Choice Feedback:
Correct. Imaging allows assessment of the extent and spread of the disease.
Choice 5: Pelvic ultrasound Score : -1
Choice Feedback:
Incorrect. Although used extensively in assessment of ovarian mass/cancer, pelvic ultrasound is rarely
used in staging/assessment of invasive cervical cancer.
Choice 6: MRI Score : 1
Choice Feedback:
Correct. MRI is extremely useful especially in determining tumour size, degree of stromal invasion,
degree of invasion (including adjacent structures such as bowel and bladder), degree of lymph node
involvement and parametrial extension.
Choice 7: CT pyelogram Score : -1
Choice Feedback:
Incorrect. CT pyelography may be indicated if there is a suggestion of renal tract obstruction - for
example by a mass lesion in the pelvis. In the first instance a standard CT scan should be undertaken.
If this shows a mass lesion in the pelvis with possible ureteric obstruction, a CT pyelogram maybe
considered.
Question 8 : SC
Question Information:
The laboratory tests return a normal full blood count, urea, creatinine, electrolyte and liver function test.
The chest X-ray is normal. Further investigation under anaesthesia reveals a clinically visible lesion
(1cm diameter) and both CT abdomen and pelvis are clear. There is no evidence of extension of the
disease into surrounding structures or lymph nodes.
Question:
Which one of the following is the most appropriate treatment?
Choice 1: Surgery Score : 1
Choice Feedback:
Correct. Given the limited extent of the disease, the treatment modality of choice is surgery.
In an older woman who has had children, the surgery performed would be a radical hysterectomy and
bilateral pelvic lymphadenectomy. However, development of fertility preserving procedures such as
radical trachelectomy has allowed for preservation of the uterus. Radical trachelectomy involves
laparoscopic dissection of pelvic lymph nodes, radical removal of the upper vagina and most or all of
the cervix.
Sarah will also require counselling. Events have progressed quite quickly and this is likely to be a shock
to Mary. It is important to have a sensitive discussion with her and discuss possible outcomes,
complications and any side-effects of treatment. This is also an important time to address any questions
she might have.
Above all, it is important to relay to Sarah that she will have support throughout this process.
Choice 2: Radiotherapy Score : -1
Choice Feedback:
Incorrect. Radiotherapy is the treatment of choice for women with more advanced stage of cervical
cancer. This should be done in conjunction with platinum-based chemotherapy.
Choice 3: Platinum-based chemotherapy Score : -1
Choice Feedback:
Incorrect. Platinum-based chemotherapy is used in conjunction with radiotherapy to treat more
advanced stages of cervical cancer. It is also used for symptom control for those presenting with distant
metastatic disease.
Choice 4: Brachytherapy Score : -1
Choice Feedback:
Incorrect. Short distance (brachytherapy) radiotherapy may be suitable for locally advanced cancers,
but only after external beam radiotherapy has been given to reduce tumour mass. This form of
treatment would not be suitable for Sarah who has early disease (Stage IB1).
Synopsis
Sarah had an approximately 2 in 100,000 chance of an invasive cervical cancer at her initial
presentation at age 24. For Australian women, the lifetime risk of developing cervical cancer is about
1%. Currently squamous cell carcinoma comprises about 75% of these cervical cancers and about 25%
are glandular (adenocarcinoma or adenosquamous). The relatively low incidence of cervical cancer in
Australia is in marked contrast to global data.
Globally, cervical cancer is the second commonest cancer of women and is responsible for many
potentially preventable deaths. The difference in the global and Australian incidence of cervical cancer
is not fully explained but may be due to differences in susceptibility to infectious diseases (in this case
oncogenic HPV virus) associated with poverty and malnutrition, differences in local prevalence of
oncogenic HPV types, and the absence of population based screening in the †œthird world†•.
Whilst a WHO-sponsored global HPV vaccination program has superficial appeal, the current vaccines
require three injections over twelve months, and in the †œthird world†• there is no infrastructure to
support the necessary record keeping and follow up. Furthermore, at present we do not know the
longevity of protection conferred by vaccination against HPV.
This module has focused on squamous cell disease of the cervix. In Australia, the incidence of
adenocarcinoma and adenosquamous carcinoma of the cervix has remained static since the
introduction of universal screening. The Pap smear is a good screening tool for squamous cell
anomalies but not for glandular cell anomalies. The reason relates to the biology and pathophysiology.
The key to understanding squamous cell carcinoma and its intraepithelial precursors is to understand:
a) the viral (HPV) etiology and
b) the concept of the transformation zone (TZ).
The TZ is the name given to that part of the (ecto)cervix that is lined until puberty by glandular
epithelium and undergoes transformation by a process called metaplasia to squamous epithelium. This
is thought to occur gradually over several years following estrogen-mediated changes in vaginal pH.
The †œtransforming†• cells appear to be vulnerable to malignant transformation if infected by
oncogenic HPV (e.g. type 16 or 18).
Most SCC†™s arise at the squamocolumnar junction, a region that is often visible at speculum
examination or, if in the cervical canal, usually †œreachable†• for cell sampling with a small brush
(eg Cytobrush). The cervix contains crypts originally lined by glandular epithelium, which may also
undergo transformation to squamous epithelium. Epithelium in crypts is not visible at colposcopy.
The standard management of intraepithelial neoplasia of the cervix is local excision biopsy of the
transformation zone by large loop diathermy (LLETZ) or laser to a depth that includes the cervical
crypts (7-10mm). Some units may use an ablative technique (laser or radical diathermy are satisfactory,
cryotherapy is not due to insufficient depth of destruction) but this has the disadvantage of not providing
a histological specimen to confirm the diagnosis made by prior colposcopically-directed cervical biopsy.
LLETZ has replaced cold knife cone biopsy as the latter technique typically removes a much larger
segment of the cervix and is thus associated with a greater risk of subsequent pregnancy-related
complications (cervical incompetence, cervical dystocia). However, if a glandular lesion is suspected
cold knife cone biopsy is indicated as, in contrast to squamous cell anomalies, glandular anomalies
typically occur higher up the cervical canal (i.e. well proximal to the SCJ) and tend to be multifocal.
The current Australian guidelines for two-yearly screening contrast with three to five yearly screening
used in other advanced countries. There is a small improvement in detection rate with more frequent
screening as utilised in Australia. Some studies indicate a small improvement in detection rate with the
use of liquid-based cytology compared with conventional smearing on a glass slide. Liquid-based
cytology has become the default standard in the UK but has not yet been adopted in Australia except
for follow up of identified HSIL.
It appears that about 1:3 women infected with oncogenic HPV will develop SCC if left untreated. Other
risk factors for SCC cervix include immunosuppression (e.g. renal transplant and HIV patients),
smoking, a history of Chlamydia cervicitis, and long-term use of the combined oral contraceptive pill.
Immunosuppressed women should probably have annual Pap smear surveillance as their risk is
substantially increased. Smoking is also thought to be a risk factor related to immunosuppressive
effects. All women with intraepithelial abnormalities and who smoke should be informed of the
association and advised this is one aspect where †œself-help†• is available, i.e. by quitting.
Unfortunately, male condoms do not appear to be effective in preventing the sexual transmission of
HPV. HPV transmits readily by scrotal-perineal contact. It is possible but as yet unproven that the
female condom may be more effective in this regard. Women should not be advised to cease the
combined oral contraceptive pill. The pill, for example, is protective for ovarian cancer and when all
cancers are considered, there is no overall increase in risk with long-term use of the pill.
The Gardasil vaccine used in Australia is a tetravalent vaccine that is expected to reduce the incidence
of SCC cervix by about 70% and to also substantially protect against genital warts. Human nature being
what it is, it is a safe prediction that the compliance rate with two-yearly screening (currently about 66%)
will fall as some women who have been vaccinated will opt out of the Pap screening program. It will be
a challenge for health authorities to maintain the relatively high participation rate of Australian women in
this program. Individual doctors can make a contribution by being aware of just how nasty late stage
cervical cancer is and counseling their patients that regular Pap smears remain a woman†™s best
defence. It is also important for doctors to be aware that for 10% of women presenting with SCC the
most recent Pap smear was normal. Any woman presenting with symptoms (e.g. postcoital bleeding)
should be referred for colposcopy even in the presence of a normal Pap smear.
A confirmed biopsy result of invasive cervical cancer would mean that the woman would have to be
referred to a multidisciplinary team including gynaecologic oncologist, radiation oncologist and others
for further investigations and treatment. The extent of the disease will be assessed and further
treatment is based on what stage the disease is at. Staging assessment for cervical cancer is a clinical
assessment, although imaging such as MRI and CT scan are also used and is based on the FIGO
(Federation Internationale des Gynaecologistes et Obstetristes) staging system. For women up to
Stage IIA disease, radical hysterectomy and bilateral lymphadenectomy is the main modality of
treatment. However, in younger women or those who want more children, radical trachelectomy is an
advancement in surgical techniques where the uterus is preserved with radical removal of upper vagina
and most or all of the cervix plus laparoscopic pelvic lymph node dissection. Radiotherapy is also an
option for earlier stages but it is still being studied further due to the resulting ovarian failure in
premenopausal women. It is more often used in conjunction with platinum-based chemotherapy for
women with more advanced staging of the disease. Unfortunately, for women who present with distant
metastasic disease, palliative care may be required and chemotherapy is used for symptom control.
The prognosis for cervical cancer is reasonable. The 5 year survival rate is more than 95%, 65%, 40%
and 15% for Stage IA, Stage II, Stage III and Stage IV respectively. There are still studies ongoing
looking at various ways to improve treatment option for cervical cancer and hopefully with the
vaccination programme underway, the rate of invasive cervical cancer will continue to decline.
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This case has been produced at the University of Adelaide. Support for its evaluation and peer review
has been provided by the Australian Learning and Teaching Council Ltd, an initiative of the Australian
Government Department of Education, Employment and Workplace Relations. The views expressed in
this case do not necessarily reflect the views of the Australian Learning and Teaching Council.
Adelaide
Dec 2011
Reviewed by Dr Amy Hercus, Sept 16