Clinical Topic A-Z Clinical Speciality

Cervical cancer and HPV

Cervical cancer and HPV
D002583Uterine Cervical Neoplasms
ImmunizationsPreventative medicineWomen's health
2010-12-06Last revised in December 2010

Cervical cancer and HPV - Summary

Types of cervical cancer include:

Squamous cell carcinoma — about 66% of cases of cervical cancer.

Cervical adenocarcinoma — 15% of cervical cancer.

Cervical cancer is caused by persistent infection with human papillomavirus (HPV). The development of CIN and cervical cancer is a continuous process: changes in the cervical epithelium become worse and in some women develop into invasive cervical cancer. Changes may regress, but this becomes less likely as the disease progresses.

Usually the progress is gradual, and the development of cervical cancer is amenable to detection and control through the cervical screening programme.

The two most important risk factors for cervical cancer are:

Acquiring infection with human papillomavirus (HPV), particularly types 16 and 18.

Inadequate cervical screening.

The risk of acquiring HPV infection depends on:

The number of sexual partners.

The age at first sexual intercourse.

The likelihood that the woman's partner or partners were infected with HPV.

Whether or not a condom is used.

Many women with cervical cancer will be asymptomatic. The possibility of cervical cancer should be considered in a woman who has any of the following nonspecific symptoms:

Intermenstrual bleeding.

Postcoital bleeding.

Postmenopausal bleeding.

Blood-stained vaginal discharge.

Pelvic pain/dyspareunia.

Rarely, women may present with advanced cancer with such symptoms as pelvic discomfort or pain, renal failure, leakage of urine or faeces from a fistula, lymphoedema, or severe haemorrhage.

On examination:

The cervix may appear inflamed or friable and bleed on contact (although the most likely cause for this will be infection with Chlamydia trachomatis).

There may be a visible ulcerating or fungating lesion or a foul-smelling serosanguineous vaginal discharge.

Referral for fast-track colposcopy should be arranged for all women in whom there appears to be a visible suspicion of cervical cancer, or an abnormal cervical cytology sample.

An urgent referral to gynaecology (within 2 weeks)should be arranged for postmenopausal women who:

Have not received hormonal replacement therapy and have vaginal bleeding.

Have persistent or unexplained vaginal bleeding after cessation of hormone replacement therapy for 6 weeks.

Referral to gynaecology or to a genitourinary medicine clinic should be arranged for premenopausal women who have:

Persistent intermenstrual bleeding, post-coital bleeding, or blood-stained vaginal discharge, and

Infection has been excluded or treated, but the bleeding has continued for 6–8 weeks post treatment, or a polyp, ectropion, cervicitis, or warts are present.

Urgent referral (within 2 weeks) should be considered for women with persistent intermenstrual bleeding and a negative pelvic examination.

Staging is based on the FIGO staging system that is universally used worldwide. In the UK, computed tomography, magnetic resonance imaging, and positron emission tomography (PET) are also used to assess the extent of the disease. Decisions on treatment are made based on the extent of the disease.

Have I got the right topic?

192months3060monthsFemale

This CKS topic is based on guidelines from the Scottish Intercollegiate Guidelines Network, Management of cervical cancer: a national clinical guideline [SIGN, 2008] and guidance from the Department of Health, Clinical practice guidance for the assessment of young women aged 20-24 with abnormal vaginal bleeding [DH, 2010].

This CKS topic covers the prevention, diagnosis, and management of cervical cancer in primary care.

This CKS topic does not cover the management of cervical intraepithelial neoplasia or the detailed management of cervical cancer in secondary care or recurrent or advanced disease. This CKS topic does not cover in detail the Childhood Immunization Programme for human papillomavirus (HPV) vaccination to prevent HPV infection.

There are separate CKS topics on Cervical screening, Chlamydia - uncomplicated genital, Gonorrhoea, Gynaecological cancer - suspected, Immunizations - childhood, Palliative cancer care - general issues, Palliative cancer care - pain, Pelvic inflammatory disease, and Vaginal discharge.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in December 2010

March 2014 — minor update. Update to the text to state that Gardasil® is the HPV vaccine of choice in line with guidance from the Department of Health [DH, 2012].

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic [BMA and NHS Employers, 2013].

September 2012 — minor update. Text revised in the Prevention of cervical cancer section to reflect the Department of Health recommendation to switch from Cervarix® to Gardasil® human papillomavirus (HPV) vaccine for the National Childhood Immunization Programme from September 2012 [DH, 2012].

September to December 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

Evidence-based guidelines published since the last revision of this topic:

ICSI (2010) Initial management of abnormal cervical cytology (Pap test) and HPV test in adult and adolescent females. Institute for Clinical Systems Improvement. www.icsi.org [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 July 2010.

Economic appraisals

An economic evaluation has been published since the last revision of this topic:

Jit, M., Chapman, R., Hughes, O., and Hong Choi, Y. (2011) Comparing bivalent and quadrivalent human papillomavirus vaccines: economic evaluation based on transmission model. BMJ 343, d5775. [Abstract] [Free Full-text]

Systematic reviews and meta-analyses

Systematic review published since the last revision of this topic:

Castellsague, X., Diaz, M., Vaccarella, S., et al. (2011) Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies. Lancet Oncology 12(11), 1023-1031. [Abstract]

Forouzanfar, M.H., Foreman, K.J., Delossantos, A., et al. (2011) Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet 378(9801), 1461-1484. [Abstract]

Lu, B., Kumar, A., Castellsague, X. and Giuliano, A.R. (2011) Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among woman: a systematic review and meta-analysis. BMC Infectious Diseases 11, 13. [Abstract] [Free Full-text]

Malagon, T., Drolet, M., Boiley, M.C. et al. (2012) Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infectious Diseases12(10), 781-789. [Abstract]

Shepherd, J.P., Frampton, G.K., and Harris, P. (2011) Interventions for encouraging sexual behaviours intended to prevent cervical cancer (Cochrane Review) The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Whitlock, E.P., Vesco, K.K., Eder, M., et al. (2011) Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Annals of Internal Medicine 155(10), 687-697. [Abstract] [Free Full-text]

Primary evidence

No new randomized controlled trials published in the major journals since 1 July 2010.

New policies

No new national policies or guidelines since 1 July 2010.

New safety alerts

No new safety alerts since 1 July 2010.

Changes in product availability

No changes in product availability since 1 July 2010.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To recognize the symptoms of possible cervical cancers

To investigate and refer appropriately

To support women with advanced cervical cancer as part of a multidisciplinary team

QOF indicators

Table 1 . Indicators related to cervical cancer and HPV in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
CS001 The contractor practice has a protocol that is in line with national guidance agreed with the NHSCB for the management of cervical screening, which includes staff training, management of patient call/recall, exception reporting and the regular monitoring of inadequate sample rates 7 -
CS002 England:The percentage of women aged 25 or over who have not attained the age of 65 whose notes record that a cervical screening test has been performed in the preceding 5 years In other countries ages are : aged 25 or over and under the age of 65 in Northern Ireland, aged 20 or over and under the age of 61 in Scotland and aged 20 or over and under the age of 65 in Wales 11 45-80%
CS003 The contractor ensures there is has a system for informing all women of the results of cervical screening tests 2 -
CS004 The contractor has a policy for auditing its cervical screening service, and performs an audit of inadequate cervical screening tests in relation to individual sample-takers at least every 2 years 2 -
Data from: [BMA and NHS Employers, 2013]

Background information

Types of cervical cancer

What types of cervical cancer are there?

Types of cervical cancer include:

Squamous cell carcinoma — about 66% of cases of cervical cancer.

Cervical adenocarcinoma — 15% of cervical cancer.

Poorly specified cancers — 15% of cervical cancer.

[Cancer Research UK, 2010b]

Causes

What causes it?

Cervical cancer is caused by persistent infection with human papillomavirus (HPV). The types which cause the highest risk include [Petignat and Roy, 2007; DTB, 2008]:

Types 16 and 18, which are responsible for about 70% of cervical cancers.

Types 31, 33, 35, 45, 52, and 58 which are responsible for a further 18% of cervical cancers.

Role of HPV in cervical cancer

How does human papillomavirus cause cancer?

Human papillomavirus (HPV) plays a crucial role in the development of cervical cancer. It has been detected in 99.7% of cervical cancers [NHS Cancer Screening Programmes, 2005]. It is usually transmitted by intimate sexual contact and it can (but does not usually) persist in anogenital tissue for a lifetime [Hartmann et al, 2003].

There are more than 130 strains or types of HPV, 40 of which affect the anogenital area [Public Health Agency of Canada, 2008]. At least 15 types are oncogenic and associated with cervical intraepithelial neoplasia (CIN), squamous cell carcinoma, and adenocarcinoma of the cervix [Koliopoulos et al, 2010]. These are known as high risk viruses [DH, 2008]. Of these, types 16 and 18 are particularly associated with cervical cancer, accounting for 70% of cervical cancers [DTB, 2008].

Oncogenic HPVs have two viral genes (E6 and E7) that can damage a normal cell's ability to control cell proliferation. Fortunately, this rarely happens. However, if viral integration, takes place then interference with ordered cell growth, failure to stop proliferation of cells, and cancer may occur [NHS Cancer Screening Programmes, 2005; SOGC, 2007]. It is possible that host factors, such as age, smoking, and immune status, modulate viral integration [Hartmann et al, 2003].

The development of CIN and cervical cancer is a continuous process: changes in the cervical epithelium become worse and in some women develop into invasive cervical cancer. Changes may regress, but this becomes less likely as the disease progresses [Koliopoulos et al, 2010]:

About one third of CIN 1 lesions progress to CIN 2.

About one half of CIN 2 lesions progress to CIN 3.

About one third of CIN 3 lesions progress to cervical cancer within 10 years.

It has been estimated that it takes more than 6 years from initial infection with HPV to develop CIN 3. About 30% of CIN 3 lesions will progress to cervical cancer over 10 years [Koliopoulos et al, 2010].

Usually infection and cervical abnormalities progress gradually, and the development of cervical cancer is amenable to detection and control through the cervical screening programme [Hartmann et al, 2003].

Persistence and recurrence

Does infection with human papillomavirus persist or recur?

Although human papillomavirus (HPV) infection may persist or recur, most genital HPV infections with high-risk oncogenic strains are transient and harmless [DH, 2008; Koliopoulos et al, 2010]:

70% of new infections will clear within 1 year.

90% of new infections will clear within 2 years.

The median duration of a new infection is 8 months.

Persistence of infection with types 16 and 18 is more common than with other high-risk oncogenic strains [DH, 2008].

Infection persists for longer in immunosuppressed women (such as women with HIV) [WHO, 2007].

Genital HPV infection does not cause a vigorous immune response, and only 50–60% of women develop serum antibodies to HPV [WHO, 2007].

It is not known for how long immunity persists after natural infection.

Re-infection with the same genotype may occur.

Risk factors

What are the risk factors?

The two most important risk factors for cervical cancer are:

Acquiring infection with human papillomavirus (HPV), particularly types 16 and 18 [WHO, 2007].

Inadequate cervical screening.

The risk of acquiring HPV infection depends on:

The number of sexual partners.

The age at first sexual intercourse. About 50% of women will have been infected with HPV within 4 years of first intercourse.

The likelihood that the woman's partner or partners were infected with HPV (determined by the number of their partners).

Whether or not a condom is used. Not using a condom increases the risk of HPV infection.

In women infected with HPV, the following factors increase the risk of progression to cervical cancer:

Smoking.

High parity (more than five full-term deliveries).

Use of the oral contraceptive pill for longer than 5 years [Smith et al, 2003].

Antibodies to herpes simplex virus 2 or Chlamydia trachomatis (women with these antibodies have a 1.5–2-fold increased risk of cervical cancer).

Women who have conditions associated with immunosuppression are at increased risk of acquiring HPV, persistent infection, precancerous lesions, and invasive cervical cancer. This includes women who have:

HIV (increases risk six fold) [Cancer Research UK, 2009].

Had an organ transplant (increases risk two-fold) [Cancer Research UK, 2009].

Inflammatory bowel disease.

The hormonal drug diethylstilbestrol (DES) was used during pregnancy in the 1940s and 1950s to boost oestrogen levels (to prevent miscarriage). Women whose mothers took DES whilst they were in utero may have a two- to three-fold risk of invasive cervical cancer [RCOG, 2002].

[NHS Cancer Screening Programmes, 2005; Alberta Medical Association, 2009]

Prevalence

How common is it?

Prevalence of cervical cancer

What is the prevalence of cervical cancer?

Pre-invasive lesions. In 2007 there were 25,033 new registrations of cervical intraepithelial neoplasia 3 (CIN 3) in the UK. Most of these (95%) were in women younger than 45 years of age [Cancer Research UK, 2010b].

Invasive cancer of the cervix. In 2007, there were 2,828 new diagnoses of invasive cancer of the cervix in the UK. Invasive cancer of the cervix is the eleventh most common cancer in women in the UK [Cancer Research UK, 2010a]. It has been estimated that the lifetime risk in the UK of developing cervical cancer is 1 in 136 [Cancer Research UK, 2010b]. The annual incidence of cervical cancer per 100,000 women by age group in England is [SIGN, 2008]:

Aged 20–24 years: 2.6.

Aged 25–34 years: 11.7.

Aged 35–44 years: 4.8.

Aged 45–54 years: 3.4.

Cervical cancer accounts for 1 in every 10 cancers diagnosed in women worldwide [Cancer Research UK, 2010a].

Prevalence of HPV infection

What is the prevalence of human papillomavirus infection?

About 10–20% of sexually active adults have HPV infection at any time [Koliopoulos et al, 2010]. Prevalence is extremely low in girls of 14 years of age but rises in the mid-teens [DH, 2008].

A study of women 10–29 years of age in England found that only 5% of girls younger than 14 years of age were seropositive for any HPV type [Jit et al, 2007]:

Seropositivity increased until the mid 20s and then declined.

The most common infection was with type 16 (12%) which is oncogenic.

Being seropositive for types 6, 11, and 18 was significantly associated with being seropositive for type 16.

Cross-sectional data from the ARTISTIC trial (A Randomized Trial In Screening To Improve Cytology) found a prevalence of high-risk HPV infection of 40% in 2575 women 20–24 years of age [Kitchener et al, 2006].

A multi-site study of the prevalence of HPV in 4719 cervical cytology samples in England found the prevalence of high-risk HPV was 16% (prevalence of oncogenic types 16 and/or 18 was 5%) [Howell-Jones et al, 2010].

It has been estimated that 50–79% of sexually active women have a lifetime risk of being infected with HPV [Cadman, 2006].

About 50% of sexually active women have evidence of past infection with HPV [Koliopoulos et al, 2010].

An epidemiological analysis of 3730 women 24–45 years of age found that women in this age group are still susceptible to new infection with HPV, and are acquiring new infections with types of HPV contained in the quadrivalent vaccine (that is types 6, 11, 16, and 18) [Velicer et al, 2009].

Prognosis

What is the prognosis?

The death rate from cervical cancer dropped significantly in the latter half of the 20th century. This is believed partly to be a result of improved treatment and early detection through the cervical screening programme [Cancer Research UK, 2010a; Cancer Research UK, 2010d]:

More than 80% of women diagnosed with cervical cancer between 2004 and 2006 have survived for more than 1 year.

About 64% of women diagnosed with cervical cancer between 2001 and 2006 have survived for more than 5 years.

About 64% of women diagnosed with cervical cancer between 1996 and 2000 have survived for more than 10 years.

Prognosis is related to the woman's [Cancer Research UK, 2010b]:

Age at diagnosis. About 86% of women diagnosed at 15–39 years of age survive for longer than 5 years, whereas 65% of women 50–59 years of age survive for more than 5 years [Cancer Research UK, 2010d]. There were 957 deaths from cervical cancer in the UK in 2008. However, only about 7% of these deaths occurred in women younger than 35 years of age, whereas most deaths from cervical cancer occurred in women in their late 70s [Cancer Research UK, 2010c].

Stage at diagnosis (see Staging).

Pregnancy does not accelerate the natural history of cervical cancer, and the prognosis is the same as that for a non-pregnant woman matched for stage, tumour type, and tumour size [SIGN, 2008].

The prognosis is poor if the disease recurs. Women who have recurrent disease have a prognosis of 6 months to 2 years [SIGN, 2008].

Cervical adenocarcinoma has a worse prognosis because an adenocarcinoma grows inside the cervical canal, and may establish a large tumour volume and is often detected late compared with squamous cell carcinoma of the cervix. Survival outcomes are not significantly different if squamous cell carcinoma and adenocarcinoma are matched by patient age, clinical state, tumour volume, and method of treatment [Giuntoli and Bristow, 2008].

Complications

What are the complications?

Psychological distress due to [SIGN, 2008]:

Coping with the shock of the diagnosis.

Loss of income.

Pain, nausea, fatigue, and disfigurement.

Complications due to the cancer, such as urinary or faecal incontinence, loss of fertility, malodour.

Guilt, which may be due to [Blomfield, 2007]:

Neglecting to attend for cytology screening or follow up.

Perceived stigma because cervical cancer is due to the human papillomavirus, which is sexually transmitted.

Sexual problems after treatment or diagnosis are common, and include loss of libido, change in sexual activity, decreased capacity for orgasm, vaginal stenosis, vaginal dryness, vaginal bleeding, dyspareunia, atrophic vaginitis, and pain [SIGN, 2008].

A survey of 256 women who had been treated for early stage (IB or IIA) cervical cancer found that vaginal changes occurred, regardless of the type of treatment [Bergmark et al, 1999].

Lymphoedema may be related to the disease or the treatment, and reported incidence rates have varied between 3.6% and 49% [SIGN, 2008].

Complications of advanced disease include [SIGN, 2008]:

Pain.

Renal failure from bilateral ureteric obstruction.

Deep vein thrombosis.

Haemorrhage (minor or major).

Malodour due to necrotic tissue.

Fistulae causing malodour are extremely distressing, but rare. They may occur as a result of progressive disease, or as a late complication of radiotherapy (occurring between 17 months and 8.1 years after treatment):

A vesicovaginal fistula presents with persistent continuous watery discharge.

A rectovaginal fistula presents with persistent continuous feculent discharge.

Radiotherapy may damage [SIGN, 2008]:

The bladder.

Late radiation effects include urinary frequency, urgency, dysuria, detrusor instability, haematuria, perforation, and fistula formation.

The ureter.

Ureteric obstruction may result from radiation ischaemia and necrosis.

The rectum.

Acute radiation proctitis: tenesmus, urgency, diarrhoea, and occasionally rectal bleeding.

Late radiation proctitis: tenesmus, urgency, diarrhoea, constipation, anal sphincter dysfunction, mucus discharge, bleeding, stricture, ulceration, and fistula formation.

Diagnosis

Diagnosis of cervical cancer and HPV

Clinical features

What are the clinical features that are suspicious of cervical cancer?

Many women with cervical cancer will be asymptomatic and are diagnosed through the NHS Cervical Screening Programme because of abnormal cervical cytology, and subsequent colposcopy and biopsy. For more information, see the CKS topic on Cervical screening.

Consider the possibility of cervical cancer in a woman who has any of the following nonspecific symptoms:

Intermenstrual bleeding.

Postcoital bleeding (risk of cervical cancer increases with age).

Postmenopausal bleeding.

Blood-stained vaginal discharge.

Pelvic pain/dyspareunia.

Rarely, women may present with advanced cancer with such symptoms as pelvic discomfort or pain, renal failure, leakage of urine or faeces from a fistula, lymphoedema, or severe haemorrhage.

On examination:

The cervix may appear inflamed or friable and bleed on contact (although the most likely cause for this will be Chlamydia trachomatis; see Differential diagnosis).

There may be a visible ulcerating or fungating lesion or a foul-smelling serosanguineous vaginal discharge.

Basis for recommendation

Basis for recommendation

Nonspecific symptoms

Information on the clinical features of cervical cancer is based on expert opinion in guidelines from the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008], a clinical review [Blomfield, 2007], and a systematic review on post-coital bleeding [Shapley et al, 2006].

Studies have shown that 16–32% of women with early-stage cervical cancer have symptoms at presentation [SIGN, 2008].

However, symptoms of cervical cancer are non-specific. For example, the prevalence of post-coital bleeding in the community is 0.7–0.9% [SIGN, 2008]. A systematic review included 16 studies of women with cervical cancer and found that the prevalence of post-coital bleeding varies between 0.7% and 39% [Shapley et al, 2006].

It is not known how many women with post-coital bleeding in the community who present to primary care are referred to secondary care [Shapley et al, 2006].

On average, only 2% of women seen in secondary care with post-coital bleeding have cervical cancer. The likelihood that a woman in the community with post-coital bleeding has cervical cancer is [SIGN, 2008]:

1 in 44,000 if 20–24 years of age.

1 in 56,000 if 25–34 years of age.

1 in 2800 if 35–44 years of age.

1 in 2400 if 45–54 years of age.

Signs

Information on clinical signs is based on expert opinion in guidelines from SIGN [SIGN, 2008] and clinical reviews [Blomfield, 2007; Petignat and Roy, 2007].

Large tumours may become infected and produce an offensive serous discharge [Blomfield, 2007].

Advanced cancer

The description of symptoms of advanced cancer is based on expert opinion in guidelines from SIGN [SIGN, 2008] and a clinical review [Blomfield, 2007].

Cervical cytology sample

Should I take a cervical cytology sample?

Unscheduled cervical screening is not recommended in any situation, including when the woman has symptoms of possible gynaecological cancer. Urgent referral and assessment of the cervix is required.

If a cervical cytology sample is taken:

Referral should not be delayed until results are available.

A negative test result should not be considered definitive and the results should not be relied upon in any circumstances.

For information on scheduled screening through the NHS cervical screening programme, see the CKS topic on Cervical screening.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert consensus in the Colposcopy and programme management: guidelines for the NHS cervical screening programme [NHS Cancer Screening Programmes, 2010] and referral guidelines for suspected cancer from the National Institute for Health and Clinical Excellence (NICE) [National Collaborating Centre for Primary Care, 2005].

An unscheduled cervical sample is also not recommended by the Scottish Intercollegiate Guidelines Network [SIGN, 2008].

Differential diagnosis

What other causes of non-specific symptoms should I consider?

Consider the following causes of non-specific symptoms:

Sexually transmitted infections. Cervicitis or pelvic inflammatory disease may present with vaginal discharge associated with post-coital or intermenstrual bleeding, dysuria, deep dyspareunia, or lower abdominal pain. It is most commonly caused by Chlamydia trachomatis, and less commonly by Gonorrhoeae neisseria.

Cervicitis caused by chlamydia (or less commonly by gonorrhoea) is characterized by an inflamed cervix which bleeds easily and may be associated with a mucopurulent discharge.

Pelvic inflammatory disease caused by chlamydia (or less commonly by gonorrhoea) is characterized by lower abdominal pain, with or without fever. Cervicitis may be seen, and adnexal tenderness and cervical excitation found on bimanual palpation.

For further information on the diagnosis, investigation, and management of sexually transmitted infections, see the CKS topics on Chlamydia - uncomplicated genital, Gonorrhoea, Pelvic inflammatory disease and Vaginal discharge.

Endometrial cancer may present with postmenopausal bleeding.

An ectropion or cervical polyps may cause post-coital bleeding.

Hormonal contraception may cause unscheduled bleeding, particularly when first prescribed.

Unscheduled bleeding is common with all forms of hormonal contraception during the first 3 months of use.

Notable bleeding is also common in the first 6 months of use with the levonorgestrel-releasing intrauterine system (LNG-IUS) or progestogen-only implants.

Basis for recommendation

Basis for recommendation

Clinical features of differential diagnoses

Information on the clinical differential diagnosis of cervical cancer is based on guidelines published by the Health Protection Agency (HPA) [HPA, 2007], the Faculty of Sexual and Reproductive Healthcare (FSRH, formerly the Faculty of Family Planning and Reproductive Healthcare [FFPRHC]), the British Association for Sexual Health and HIV [FFPRHC and BASHH, 2006], the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008], and a systematic review that found post-coital bleeding may be associated with a cervical ectropion or a cervical polyp [Shapley et al, 2006].

Hormonal contraception

This information on hormonal contraception and intermenstrual bleeding is based on expert advice in guidelines published by the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit, in collaboration with the Royal College of Obstetricians and Gynaecologists [FSRH and RCOG, 2009].

Referral

Who should I refer on suspicion of cervical cancer?

Where appropriate, exclude other diagnoses that may cause non-specific symptoms that may be presenting features of cervical cancer, for example hormonal contraception or sexually transmitted infection (see Differential diagnosis). Always consider the need for a pregnancy test.

Refer for fast-track colposcopy all women in whom there appears to be a visible suspicion of cervical cancer, or an abnormal cervical cytology sample. Do not delay referral because of a previously negative cervical cytology result.

Refer urgently to gynaecology (within 2 weeks) postmenopausal women who:

Have not received hormonal replacement therapy and have vaginal bleeding.

Have persistent or unexplained vaginal bleeding after cessation of hormone replacement therapy for 6 weeks.

Refer to gynaecology or genitourinary medicine clinic, premenopausal women who have:

Persistent intermenstrual bleeding, post-coital bleeding, or blood-stained vaginal discharge, and

Infection has been excluded or infection had been treated, but the bleeding has continued for 6–8 weeks post treatment.

Polyp, ectropion, cervicitis, or warts.

Consider urgent referral (within 2 weeks) for women with persistent intermenstrual bleeding and a negative pelvic examination.

Hormonal contraception commonly causes unscheduled bleeding, and clinical judgement is necessary. Always exclude infection. Consider referral to a gynaecologist (within 2 weeks) if there are features in the history that raise the possibility of cervical cancer:

The woman has not participated in the national cervical screening programme.

Bleeding continues beyond 3 months (6 months may be acceptable if the woman is using the levonorgestrel-releasing intrauterine system [LNG-IUS] or progestogen-only implants).

The woman has new symptoms or a changed bleeding pattern.

The woman has tried contraceptive modification but unscheduled bleeding persists.

Basis for recommendation

Basis for recommendation

Pregnancy exclusion

This recommendation to rule out pregnancy is based on expert advice from guidelines published by the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit in collaboration with the Royal College of Obstetricians and Gynaecologists [FSRH and RCOG, 2009].

Referral for signs of cervical cancer

The National Institute for Health and Care Excellence (NICE) advises urgent referral for all women in whom examination of the cervix raises the suspicion of cervical cancer [NICE, 2005].

Referral for postmenopausal bleeding

Both guidelines from NICE [NICE, 2005] and from the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008] advise urgent referral for all women with postmenopausal bleeding. NICE adds that if a woman on hormone replacement therapy still has bleeding after cessation of hormone replacement therapy for 6 weeks, an urgent referral should be made [NICE, 2005].

Referral for post-coital bleeding, intermenstrual bleeding, and blood-stained vaginal discharge

These referral recommendations are based on guidelines from SIGN [SIGN, 2008] and guidelines on the Clinical practice guidance for the assessment of young women aged 20-24 with abnormal vaginal bleeding developed by a working subgroup of the Advisory Committee on Cervical Screening and published by the Department of Health [DH, 2010].

The scope of the guidelines from SIGN is for women of all ages, whereas the Department of Health guidelines are focussed on younger women who are not yet eligible for cervical screening. Although SIGN did not discuss intermenstrual bleeding, its recommendations do not contradict the Department of Health guidelines; therefore CKS have extrapolated the recommendations from the Department of Health to all women [DH, 2010].

Neither guidelines discuss the management of blood-stained vaginal discharge. However, CKS considers this symptom should be managed as for intermenstrual bleeding.

NICE also advises considering urgent referral for all women with persistent intermenstrual bleeding and a negative pelvic examination [NICE, 2005].

Excluding infection

Guidelines on the Clinical practice guidance for the assessment of young women ages 20–24 with abnormal vaginal bleeding developed by a working subgroup of the Advisory Committee on Cervical Screening and published by the Department of Health [DH, 2010] recommend taking swabs or for sexually transmitted infection or referring to a genito-urinary medicine clinic all women 20–24 years of age with post-coital bleeding, and referring them to gynaecology or genito-urinary medicine if the bleeding persists for 6–8 weeks after treatment.

Guidelines from the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008] recommend testing all premenopausal women for Chlamydia trachomatis.

Referral for cervical ectropion or cervical polyps

Referral recommendations are based on guidelines published by the Department of Health [DH, 2010]. Although post-coital bleeding is often attributed to the existence of a cervical ectropion or cervical polyps, a systematic review found little evidence for this [Shapley et al, 2006]. The review reported:

A cross-sectional study that included 151 women with a large cervical ectropion found that only 5% reported post-coital bleeding [Goldacre et al, 1978]. The author commented that a cervical erosion should not be assumed to be the cause of post-coital bleeding.

Two studies found an association between post-coital bleeding and cervical polyps:

One study of 134 women with post-coital bleeding found that 5% had a cervical polyp [Rosenthal et al, 2001].

Another study of 248 women with post-coital bleeding found that 13% had a cervical polyp [Selo-Ojeme et al, 2004].

However, the authors commented that these studies lacked controls and suffered from selection bias.

CKS has therefore advised referral to a gynaecologist for management of these conditions and exclusion of another underlying cause (including cervical cancer).

Women taking hormonal contraception

Recommendations for considering referral in women receiving hormonal contraception is based on expert opinion from guidelines published by the Department of Health [DH, 2010] and guidelines from the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit in collaboration with the Royal College of Obstetricians and Gynaecologists [FSRH and RCOG, 2009].

Management

Management

Scenario: Prevention : covers measures that can be taken to prevent infection with human papillomavirus infection, including immunization and advice on safer sex.

Scenario: Management : covers the treatment of confirmed cervical cancer in secondary care and management of specific problems associated with advanced cervical cancer in primary care.

Scenario: Prevention

Scenario: Prevention of cervical cancer

192months3060monthsFemale

Prevention

How can cervical cancer be prevented?

Where appropriate:

Encourage women to participate in the NHS cervical screening programme — available to women 25–64 years of age in England. See the CKS topic on Cervical screening.

Encourage girls aged 12–13 years to receive immunization with the human papillomavirus (HPV) vaccine as part of the Childhood Immunization Programme.

Gardasil® quadrivalent vaccine (covering HPV types 16 and 18, and types 6 and 11 giving additional protection against genital warts) should be used.

For optimum effectiveness, HPV vaccination must be given before the woman becomes sexually active.

For more information, see the section on Immunization schedule in the CKS topic on Immunizations - childhood.

Inform women about practising safe sex and the use of condoms. Explain that:

Condom use may lower the risk of HPV, but does not offer full protection, as HPV can infect areas not covered by a condom.

Condoms also protect against other sexually transmitted diseases, which are a risk factor for progression of cervical cancer (for example HIV).

Limiting the number of sexual partners reduces potential exposure to HPV infection.

Screening for HPV is not currently used in routine practice.

Basis for recommendation

Basis for recommendation

Human papillomavirus (HPV) immunization

Human papillomavirus (HPV) vaccines are intended to be prophylactic, not therapeutic. Protection rates are lower in women who have already been infected with the vaccine-related genotypes [WHO, 2007]. It is therefore important to vaccinate girls before they become sexually active [DTB, 2008]. The National Childhood Immunization Programme offers immunization for girls of 12–13 years of age [DTB, 2008; DH, 2012].

Controlled trials have indicated that the HPV vaccine Gardasil® (quadrivalent) is highly effective at preventing susceptible women from being infected with HPV types 6, 11, 16, and 18 [WHO, 2007; DH, 2012]. Studies found:

90% fewer persistent infections with genotypes 16 or 18.

That the HPV vaccine is over 99% effective at preventing pre-cancerous lesions associated with HPV types 16 and 18 in young women. Studies suggest that protection is maintained for at least 7 years, but the results of long term follow-up studies are awaited.

Gardasil® is the vaccine of choice for the national immunisation programme as this vaccine is also 99% effective in preventing genital warts associated with HPV types 6 and 11 in young women [DH, 2012].

A multi-site study of HPV type-specific prevalence in women with cervical cancer, cervical intraepithelial neoplasia, and normal cervical cytology in England found that non-vaccine HPV types (that is types 16 and/or 18) were found in 60% of women with mild dyskaryosis or less, but in fewer than 20% of women with cervical cancer. The authors commented that these results suggested that the HPV vaccine should have a marked impact on cervical disease in England [Howell-Jones et al, 2010].

It is not known how long protection lasts and whether booster doses are necessary [DTB, 2008]. Levels of antibodies to HPV are low or non-existent after infection, because HPV only has a mucosal phase and not a bloodstream phase. Levels of antibody after vaccination are much higher than after natural infection. This differs from other viral vaccines, and therefore it is not possible to predict from experience the expected length of time for protection against HPV infection [WHO, 2007].

A follow-up study of 383 women who had received three doses of HPV-16/18 virus-like particle vaccine and 393 women who had received a placebo found sustained high levels of antibodies at 4.5 years of follow up [Harper et al, 2006].

A follow-up study of 17622 women who had received the quadrivalent vaccine found that the vaccine had provided sustained protection for 42 months [The Future I/II Study Group, 2010].

There is some cross-protection against other genotypes from both the bivalent and the quadrivalent vaccines [WHO, 2007; DH, 2012].

Bivalent vaccine: cross-protection demonstrated against two other genotypes has been demonstrated in HPV-naive women.

Quadrivalent vaccine: neutralizing antibodies against genotypes 31 and 45 have been demonstrated.

Safer sex measures

This information is based on expert advice from the Centers for Disease Control and Prevention [CDC, 2009] and the World Health Organization [WHO et al, 2007].

Human papillomavirus screening

HPV screening or testing is not presently used in routine practice. However, the potential benefits of introducing HPV testing into the cervical screening programme are currently under investigation [NHS Cancer Screening Programmes, 2010]. HPV testing may be used:

In women who have either a borderline or mild dyskaryosis result:

This is called 'HPV triage'. Under the current cervical screening programme, women with these abnormalities are recalled every 6 months and/or have colposcopy, often generating anxiety. However, only 15–20% of these women will need treatment for cervical intraepithelial neoplasia 2 (CIN 2) or worse. If the woman does not have a high-risk strain of HPV present, then there is only a negligible risk that she will need treatment. Preliminary results from the sentinel site pilot studies suggest that management could be tailored to these two groups of women, depending on whether they are at high or negligible risk. Those at negligible risk could return to the normal recall programme, whereas those at high risk would have immediate colposcopy [NHS Cancer Screening Programmes, 2008].

In women who have had treatment for CIN:

This is called 'test of cure'. Of women who develop cervical cancer in the UK, 16% have had previous treatment for CIN. After treatment for CIN, women are tested for both abnormal cells (cervical cytology) and HPV. If these tests are negative, then the woman is returned to the normal screening programme instead of being followed up with annual screening for 10 years.

Research is continuing to determine the optimum time to do these tests. Expert opinion in guidelines for the NHS cervical screening programme is that there is some evidence to suggest that the HPV test should be done 6 months after treatment for CIN, followed by a combined cervical cytology and HPV test 12–18 months after treatment. If all three of these tests are negative, then the woman may be returned to routine recall [NHS Cancer Screening Programmes, 2010]. 

The potential benefits of population screening are also being investigated, although it is not currently recommended for routine use. It is likely that HPV testing may be particularly useful because of its high negative predictive value. This means that a high proportion of women with a negative test result do not have CIN, and there is a high probability that this result is correct. Good evidence from a randomized controlled trial [Kitchener et al, 2009] indicates that HPV testing combined with cervical cytology is not cost effective. However, the trial highlighted the possibility of initial HPV testing with cervical cytology reserved for women who have a positive HPV result. HPV testing does not seem to cause significant psychosocial distress.

Scenario: Management

Scenario: Management of cervical cancer and HPV

192months3060monthsFemale

Staging

How is cervical cancer staged in secondary care?

Cervical cancer is staged on clinical findings using the FIGO (Fédération Internationale des Gynaecologistes et Obstetristes) criteria. Treatment is defined according to the stage of the disease. It is acknowledged that clinical staging alone is inaccurate, and in the UK clinicians allow information obtained from modern medical imaging, as well as FIGO staging, to influence their management. However, the FIGO system remains to allow comparisons to be made worldwide, as most cervical cancer occurs in developing countries.

Stage 0: cervical intraepithelial neoplasia (CIN) 3: carcinoma in situ; pre-invasive cancer.

Stage I: the cancer remains within the cervix and uterus.

Stage IA: diagnosed only by microscopy.

Stage IA1: measured stromal invasion of not more than 3 mm in depth, and extension of not more than 7 mm.

Stage IA2: measured stromal invasion of between 3 mm and 5 mm in depth, and extension of not more than 7 mm.

Stage IB: clinically visible lesions confined to the cervix, or preclinical cancers greater than 1A.

Stage IB1: clinically visible lesions not more than 4 cm in the greatest dimension.

Stage IB2: clinically visible lesions more than 4 cm in the greatest dimension.

Stage II: the cancer has begun to spread into the tissues surrounding the cervix.

Stage IIA: no obvious parametrial involvement (the parametrium is the connective tissue of the pelvic floor extending from the fibrous subserous coat of the supracervical portion of the uterus, laterally between the layers of the broad ligament).

Stage IIB: obvious parametrial involvement.

Stage III: the cancer has spread within the pelvis.

Stage IIIA: the tumour involves the lower third of the vagina but not the pelvic side wall.

Stage IIIB: spread to the pelvic side wall. Includes hydronephrosis and non-functioning kidney.

Stage IV: the cancer has spread to other body organs beyond the pelvis or has involved the mucosae of the bladder or rectum.

Stage IVA: spread of the growth to adjacent organs.

Stage IVB: spread to distant organs.

[Pugh, 2000; Petignat and Roy, 2007; Cancer Research UK, 2010b]

Basis for recommendation

Basis for recommendation

This information is from expert review articles [Blomfield, 2007; Petignat and Roy, 2007].

Treatment

How is cervical cancer treated in secondary care?

Staging is based on the FIGO staging system that is universally used worldwide. In the UK, computed tomography, magnetic resonance imaging, and positron emission tomography (PET) are also used to assess the extent of the disease. Decisions on treatment are made based on the extent of the disease.

In women with cervical intraepithelial neoplasia (CIN) (FIGO stage 0):

Colposcopy.

Biopsy and histological analysis.

If moderate to severe abnormalities are found: excision or ablation.

In women with early cervical cancer (FIGO stages IA1, IA2, and IB1):

Surgery is the treatment of choice for women with early cervical cancer:

Simple hysterectomy or radical hysterectomy, depending on the stage of cancer.

If there is pelvic lymph node involvement, concomitant chemotherapy and radiotherapy may be used.

If the woman wishes to preserve her fertility, then options (depending on the stage and whether lymphatic-vascular space invasion is present) include:

Radical trachelectomy (removal of the upper vagina, the cervix with parametrial tissue after pelvic lymphadenectomy, with preservation of the uterus). Pelvic lymphadenectomy may be done laparoscopically.

Cold-knife conization, or large-loop excision of the transformation zone (LLETZ), with or without pelvic lymph node dissection.

In women with late cervical cancer (FIGO stages IB2, IIA, IIB, IIIA, IIIB and IVA):

Combined chemotherapy and radiotherapy is the treatment of choice.

Surgery is not suitable because of the risk of positive margins (that is there are cancer cells at the edge of the tissue that has been removed) and positive lymph nodes.

In women with advanced cervical cancer (FIGO stage IVB):

Only palliative treatment is possible.

Platinum-based combination chemotherapy has potential benefits for some women.

In women who are pregnant:

If the woman has early-stage disease (FIGO stages IA1, IA2, IB):

If before 16 weeks' gestation, immediate treatment is advised.

If after 16 weeks' gestation, delivery may be delayed until the fetus has matured.

If the woman has late-stage disease (FIGO stage IB2 or more advanced):

If before 20 weeks' gestation, immediate delivery and treatment of disease is advised.

If after 20 weeks' gestation, delivery and treatment should be initiated within 4 weeks. Consideration for delay should be based on the gestational age and the woman's wishes.

If the cervical cancer recurs, then the options are:

Surgery (salvage): pelvic exenteration is possible if the relapse is confined to the central pelvis and chemotherapy and radiotherapy have failed.

Chemotherapy — palliative.

Supportive care only.

Basis for recommendation

Basis for recommendation

Treatment of non-pregnant women

This information is based on guidelines from the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008], a summary of the SIGN guidelines [James et al, 2008], the European Society for Medical Oncology (ESMO) clinical recommendations for diagnosis treatment and follow up [Haie-Meder et al, 2009], information from Drug and therapeutics bulletin [DTB, 2008], and a clinical review [Blomfield, 2007].

Treatment of pregnant women

This information is based on guidelines from SIGN [SIGN, 2008].

Treatment of recurrent disease

This information is based on guidelines from SIGN [SIGN, 2008].

Advanced disease

What specific problems are associated with advanced cervical cancer?

Women with incurable cervical cancer should be managed on an individual basis with the primary healthcare professional as part of a multidisciplinary team. For general information on primary care management at the end of life, see the CKS topic on Palliative cancer care - general issues.

Primary care clinicians should be aware of the distressing problems that are associated specifically with advanced cervical cancer for whom the following treatments may be appropriate.

Pain — early specialist referral for consideration of:

Nerve-blocking procedures in addition to analgesics.

Spinal therapy (using opiates, local anaesthetics, and clonidine) to provide regional blockade for pelvic pain, pain from bony metastases, or neuropathic pain.

Percutaneous cementoplasty for bony metastases.

Renal failure due to ureteric obstruction — options include:

No treatment.

Percutaneous nephrostomy.

Retrograde stenting.

Bleeding and thrombosis problems:

Deep vein thrombosis — low-molecular-weight heparin is more effective than oral anticoagulants.

Minor vaginal bleeding — may respond to oral or topical tranexamic acid or radiotherapy.

Massive haemorrhage may occur due to erosion of a major artery, and may lead to death. Relieve distress promptly and discuss management with the multidisciplinary team. Consider using midazolam for its anxiolytic effect, or diamorphine for its hypotensive effect, if admission is not deemed to be appropriate.

Malodour — management is dependent on the cause.

If due to necrotic tissue. consider surgical debridement.

If it is due to fistula-related faecal incontinence, consider referral for defunctioning colostomy.

If it is due to fistula-related urinary incontinence, consider referral for bilateral percutaneous nephrostomy.

Lymphoedema of the legs.

Refer to a specialist for consideration of conservative treatments, such as decongestant lymphatic therapy with compression bandaging, manual lymph drainage, and massage, and ensure good skin care and exercise.

Ensure prompt treatment of cellulitis.

Give advice about avoidance of injury.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in guidelines from the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008].

Low-molecular-weight heparin

This recommendation is based on expert opinion in guidelines from the SIGN [SIGN, 2008] and is based on the results of a randomized controlled trial. People with cancer who had also had a deep vein thrombosis or a pulmonary embolism were randomized to receive either low-molecular-weight heparin (dalteparin) for 5–7 days followed by a coumarin derivative for 6 months (338 people) or low-molecular-weight heparin (dalteparin) alone for 6 months (338 people). It was found that dalteparin alone was more effective at reducing the risk of recurrent thromboembolism without increasing the risk of bleeding [Lee et al, 2003].

Evidence

Evidence

Supporting evidence

This topic is largely based on national guidelines, including the following:

Referral guidelines for suspected cancer: quick reference guide, published by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2005].

Management of cervical cancer: a national clinical guideline, published by the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2008].

Clinical practice guidance for the assessment of young women ages 20–24 with abnormal vaginal bleeding, developed by a working subgroup of the Advisory Committee on Cervical Screening and published by the Department of Health [DH, 2010].

Evidence on diagnostic investigations and treatment interventions are not summarized, as the decisions to use these are made in secondary care.

Search strategy

Scope of search

A full literature search was not requested as this CKS topic is primarily based on the Scottish Intercollegiate Guidelines Network Management of cervical cancer [SIGN, 2008] and Department of Health Clinical practice guidance for the assessment of young women aged 20–24 with abnormal vaginal bleeding [DH, 2010]. Additional searches were requested for further evidence in the following areas:

Diagnosis and management of cervical cancer

Search dates

Date unrestricted – July 2010

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

cervical cancer.tw., exp Uterine Cervical Neoplasms/, cervical carcinoma.tw., cervical neoplasm.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

Cancer Research UK

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

NICE Evidence

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Royal Australian College of General Practitioners

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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