Cervical Carcinoma

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Synonyms: cervical cancer, cancer of the (uterine) cervix, carcinoma of the (uterine) cervix

Worldwide, cervical carcinoma is the second most common female malignancy, causing approximately 500,000 new cases each year.[1] It is responsible for 274,000 deaths and is the third most common cause of female mortality. In Europe the crude mortality rate is 5.9/100,000 women/year but the mortality rate is 10 times higher in developing countries.

It has been proven that the cervical screening programme is associated with improved rate of cure of cervical cancer.[2]

Incidence

The age-standardised (European) annual incidence rate of cervical cancer is 13.2 per 100,000 females.[1] Age-standardised mortality rate for the UK was 2.9 per 100,000 in 2008.[3]

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Risk factors

  • Heterosexual women.
  • Infection with human papilloma virus (HPV), predominantly types 16 and 18 (infection present in around 95% of cases).[4]
  • Women with multiple sexual partners, or partners of promiscuous males.
  • Smoking.
  • Lower social class.
  • Immunosuppression ,eg HIV, and post-transplant.
  • There is a slight increase in risk with use of a combined oral contraceptive.
  • Non-attendance at the cervical screening programme.

Three types of primary tumour are generally seen:

  • Bulky, ectocervical tumour, which fills the upper vagina.
  • Invasive, bulky tumour that can enlarge to a size where it fills the lower pelvis.
  • Destructive, invasive tumour that erodes tissue, causing ulceration and excavation with infected, necrotic cavities.

Histopathology

70% are squamous carcinomas, 15% mixed pattern, and 15% adenocarcinoma, all three of which cause both pre-invasive and invasive disease.

Cervical intraepithelial neoplasia (CIN) - disease confined to the epithelium

CIN I : disease confined to the lower third of the epithelium. CIN II: disease confined to the lower and middle thirds of the epithelium. CIN III: affecting the full thickness of the epidermis.

Invasive carcinoma

This breaches the epithelial basement membrane at any point.

  • If the deepest invasive element is <5 mm from the surface of the epithelium then it is defined as micro-invasive carcinoma.
  • If it extends beyond 5 mm or is wider than 7 mm then it is defined as invasive carcinoma and formal staging is required.

Many cases are detected by screening. However, symptoms require full pelvic examination including use of a speculum.

The first symptoms of established cervical carcinoma are:

  • Vaginal discharge; this varies greatly in amount and can be intermittent or continuous.
  • Bleeding; this can be spontaneous but may occur after sex, micturition or defecation, in the early stages. Patients may ignore this if it is scanty and ascribe it to normal menstrual dysfunction. Occasionally, severe vaginal bleeding may necessitate emergency hospital admission.
  • Vaginal discomfort/urinary symptoms.

Late symptoms

  • Painless haematuria.
  • Chronic urinary frequency.
  • Painless fresh rectal bleeding.
  • Altered bowel habit.
  • Leg oedema, pain and hydronephrosis leading to renal failure are ominous, late signs indicating pelvic wall involvement.
  • With more advanced disease, patients develop pelvic discomfort or pain that is poorly localised and described as dull or boring in the suprapubic or sacral regions. It is similar to menstrual discomfort, can be persistent or intermittent and may be confused with arthropathy.

NB: symptoms may prompt the patient to seek a cervical smear. A smear test is useful for detecting precancerous lesions, but not carcinoma. If there is any degree of suspicion of cervical carcinoma then examine carefully and consider urgent referral for further assessment.

Signs

In early-stage cervical cancer, examination can be relatively normal.

  • There may be white or red patches on the cervix. As the disease progresses, it can lead to an abnormal appearance of the cervix and vagina, due to erosion, ulcer or tumour.
  • Rectal examination may reveal a mass or bleeding due to erosion.
  • Bimanual palpation may reveal pelvic bulkiness/masses due to pelvic spread.
  • Leg oedema may develop due to lymphatic or vascular obstruction.
  • Hepatomegaly may develop in the case of liver metastases.
  • Pulmonary metastases are normally only detected if they cause pleural effusion or bronchial obstruction.
  • Cervicitis.
  • Dysfunctional uterine bleeding.
  • Cervical erosion (ectropion).
  • Pelvic inflammatory disease.
  • Endometrial carcinoma.
  • Side-effects of intrauterine contraceptive device (IUCD) use.
  • Endometrial hyperplasia.
  • Fibroids.
  • Atrophic vaginitis.
  • Premenopausal women presenting with abnormal vaginal bleeding should be tested for Chlamydia trachomatis.[5]
  • Postmenopausal women should be referred urgently to gynaecology for assessment.
  • Colposcopy - allows examination of the visible cervix, usually including the transformation zone:
    • The cervix is first cleaned with acetic acid.
    • The cervix can then be inspected, biopsied and treated if necessary.
  • Cone biopsy.
  • FBC (for anaemia) - haemoglobin level should be monitored during chemoradiotherapy and corrected if it falls below 12 g/dL.
  • Renal function tests, LFTs.
  • CXr (to seek metastases) and IV urogram.
  • CT scanning of the pelvis and abdomen - used to stage disease, along with relevant biopsies.
  • Barium enema or proctoscopy - used to assess rectal compression/invasion.
  • Cystoscopy - to assess bladder invasion.
  • MRI - gives a clear picture of a primary tumour, local invasion and nodal enlargement.

The staging system of the International Federation of Gynecology and Obstetrics (FIGO) is most commonly used.[1]

  • 0: carcinoma in situ (pre-invasive).
  • I: cervical carcinoma confined to the cervix (disregard extension to corpus).
    • Ia: invasive carcinoma diagnosed only by microscopy (all visible lesions, even superficial ones are 1B).
      • Ia1: stromal invasion to maximum 3 mm depth and 7 mm horizontal spread.
      • Ia2: stromal invasion >3 to <5 mm with 7 mm horizontal spread.
    • Ib: clinical visible lesions confined to the cervix or lesion visible on microscopy >IA2.
      • Ib1: clinically visible lesion 4 cm in largest dimension.
      • Ib2: clinically visible lesion >4 cm in largest dimension.
  • II: tumour invades beyond the uterus but not to the pelvic wall or the lower third of the vagina.
    • IIa: no parametrial invasion.
    • IIA1: clinically visible lesion ≤4.0 cm in greatest dimension.
    • IIA2:clinically visible lesion ≥4.0 cm in greatest dimension.
    • IIb: parametrial invasion (but not the pelvic sidewall).
  • III: tumour extends to the pelvic wall and/or involves the lower third of the vagina and/or causes hydronephrosis or the kidney not to function.
    • IIIa: tumour involves the lower third of the vagina - no extension to the pelvic wall.
    • IIIb: tumour extends to the pelvic wall and/or causes hydronephrosis or the kidney not to work.
  • IV: further spread.
    • IVa: tumour invades the mucosa of the bladder or rectum and/or extends beyond the true pelvis.
    • IVb: distant metastases.

In pregnancy, treatment may be delayed until a viable fetus can be delivered (provided this delay is only for a few weeks) or a therapeutic abortion may be necessary.

Surgical

The extent of surgery will be dictated by the tumour stage, the age of the patient and comorbidities. For example, for FIGO stage IA1, standard treatment consists of conisation with free margins or simple hysterectomy (according to the patient's age).

  • Destruction/excision of abnormal ectocervical epithelium during colposcopy is used for intraepithelial neoplasia confined to the visible ectocervix:
    • Cautery, cryosurgery, and laser can be used, but loop diathermy is now considered the best approach (it provides a specimen for histology).[6]
    • The patient may experience discomfort, discharge and, occasionally, bleeding but it does not cause cervical incompetence or prevent pregnancy.
    • Healing should be complete in three months and visible on repeat colposcopy.
    • Annual follow-up cytology.
  • Cone biopsy is needed where cytology suggests cervical intraepithelial neoplasia (CIN) with extension above the reach of colposcopy but ectocervical invasive disease not apparent:
    • The operation removes the ectocervix and most of the endocervix in a single doughnut-shaped piece of tissue.
    • With proper wound closing and reconstruction of the cervix, healing is quick with few symptoms apart from light central pelvic discomfort and light vaginal discharge.
    • Providing the internal os is undamaged, pregnancy is still possible.
    • This procedure is sufficient if pathology shows that abnormality was confined to the epithelium and the margins of both the ectocervix and endocervix are clear of disease.
    • Indefinite annual follow-up cytology.
  • Radical trachelectomy involves removal of the cervix with parametrial tissue after pelvic lymphadenectomy. It is a curative procedure designed to retain fertility in young women with early-stage cervical cancer (tumour size ≤4 cm). Cure rates are comparable to radical hysterectomy, and women who later try to conceive have more than a 50% chance of pregnancy.[7]
  • Hysterectomy without significant parametrial or nodal dissection is suitable for patients otherwise suitable for cone biopsy or who have micro-invasive disease only, but do not wish to become pregnant.
    • Removal of pelvic lymph nodes is not recommended during treatment for FIGO 1a1 disease.
    • Pelvic lymph nodes should be removed if FIGO 1a2 disease is present.[5] This may be performed laparoscopically.
    • Histology may show the presence of more extensive disease than expected and the patient will need postoperative radiotherapy. There is a low risk of postoperative complications.
  • Laparoscopic radical hysterectomy is performed for stage I and IIA cervical cancer.
    • The National Institute for Health and Clinical Excellence (NICE) guidance is that current evidence on the safety and efficacy of this procedure is inadequate to support its use, without special arrangements for consent or audit/research with clinical governance oversight.[8]
    • Laparoscopic-vaginal radical hysterectomy should not be offered to patients with a tumour diameter greater than 2 cm.[5]
  • Radical (Wertheim's) hysterectomy:
    • This aims to provide definitive treatment for invasive, infiltrating and early metastatic carcinoma.
    • It involves excision of the primary tumour with a 1 cm margin of healthy tissue and en bloc resection of the main pelvic lymph node areas.
    • It may involve removal of the upper third of the vagina and uterovesical and uterosacral ligaments.
    • Bladder function returns only slowly and may cause chronic retention.
    • Occasionally, painful lymphocysts develop requiring drainage.
  • Anterior, posterior or total pelvic exenteration:
    • All involve removal of pelvic adnexae plus removal of the bladder and/or rectosigmoid, with possible creation of one or two stoma.
    • The patient needs to be relatively fit and able to withstand very destructive surgery.

Radiotherapy

For FIGO stage IB2-IVA, concomitant chemoradiation (platinum-based chemotherapy) represents the standard treatment.[1]

Generally, a combination of external beam therapy and intracavity brachytherapy is used.

  • External beam therapy uses megavoltage with the uterus, cervix and primary tumour involved and may extend from the true pelvic floor up to the upper sacrum and occasionally the para-aortic regions. Generally, external beam therapy is given at the start of the course of treatment and intracavity therapy towards the end. The external beam dose is usually 40-60 Gy given in daily doses over 4-6 weeks.
  • Intracavity brachytherapy can be given earlier if the patient is bleeding heavily, and can be used on its own in older patients with stage I or stage IIa disease, up to 2 cm in diameter. Therapy may be low-dose, medium-dose or high-dose. The advantage of high-dose is that it has a short delivery time (a few minutes) compared with 2-3 days for low-dose.[9] This reduces necessary inpatient time and staff exposure to radiation. Intracavity therapy is not suitable for patients with destructive disease or for those with a stump carcinoma arising from an earlier hysterectomy.

Complications:

  • The most common acute reaction to radiotherapy is a change in bowel frequency, including diarrhoea starting 10-14 days after treatment begins and lasting for 3-4 weeks after it stops.
  • More acute bowel reaction may require treatment for subacute obstruction.
  • Most commonly, patients experience dysuria and frequency, which often settles quickly.
  • Lymphoedema - patients with symptoms suggestive of lymphoedema should be referred to a lymphoedema practitioner and be offered decongestive lymphatic therapy if symptoms are severe or poorly controlled.

Pharmacotherapy

Cisplatin-based chemotherapy has been used with some success:

  • It can be given concurrently with radiotherapy in women with stage Ib2-IVa disease, where radiation is the primary treatment.
  • It is also given to women with stage I/IIa disease with poor prognostic factors, such as lymph node involvement or positive surgical margins.

It has been shown to reduce the risk of recurrence and death by 30-50%. However, toxicity is high and it is only suitable for high-risk patients who are otherwise fit. In recurrent or metastatic disease that is unsuitable for surgery or radiotherapy, but otherwise suitable for chemotherapy, offer a trial of active chemotherapy. Topotecan in combination with cisplatin is recommended as a possible treatment for women with recurrent or stage IVB cervical cancer only if they have not received cisplatin before.[10]

  • If there is an initial symptomatic response, eg relief of pain and leg oedema together with objective response, then offer a full 6-8-month course.
  • There is only good partial or complete remission in 20-25% patients, and this is unlikely to last more than three years.

Neoadjuvant chemotherapy remains controversial.

Chemoradiotherapy

  • The addition of concurrent cisplatin-based chemotherapy to radiotherapy significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.[11]
  • The timing and dose intensity of cisplatin-based neoadjuvant chemotherapy before radiotherapy appears to have an important impact on its beneficial effects and requires further research.[12]

Follow-up

There is no clear evidence base to define this, but standard practice is clinical with gynaecological examination including PAP smear every three months for the first two years, every six months for the next three years and yearly thereafter.[1] It should be noted that frequent vaginal vault cytology does not add significantly to the detection of early disease recurrence.[13] Patients should return to annual population-based screening after five years of recurrence-free follow-up.

Approximate 5-year survival depends upon the stage.

Stage 5-year survival rate[14] (%)
Ia1
Ia2
98-99%
95-98%
Ib1
Ib2
90-95%
80%
IIa
IIb
70-90%
60-70%
IIIa/b 30-50%
IVa >20%
IVb <20%

Further reading & references

  1. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2010)
  2. Andrae B, Andersson TM, Lambert PC, et al; Screening and cervical cancer cure: population based cohort study. BMJ. 2012 Mar 1;344:e900. doi: 10.1136/bmj.e900.
  3. Cervical cancer - UK mortality statistics, Cancer Research UK
  4. F. Xavier Bosch & Thomas Iftner The Aetiology of Cervical Cancer, NHSCSP Publication No 22 September 2005
  5. Management of cervical cancer, Scottish Intercollegiate Guidelines Network - SIGN (January 2008)
  6. Colposcopy and Programme Management: Guidelines for the NHS Cervical Screening Programme; NHS Cancer Screening Programme (2010)
  7. Petignat P, Roy M; Diagnosis and management of cervical cancer. BMJ. 2007 Oct 13;335(7623):765-8.
  8. Laparoscopic radical hysterectomy for early stage cervical cancer, NICE Interventional Procedure Guideline (May 2010)
  9. High dose rate brachytherapy for carcinoma of the cervix, NICE (2006)
  10. Topotecan for the treatment of recurrent carcinoma of the cervix, NICE Technology Appraisal Guideline (October 2009)
  11. Green J, Kirwan J, Tierney J, et al; Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002225.
  12. Cochrane database of Systematic Reviews; Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration (NACCCMA) Neoadjuvant chemotherapy for locally advanced cervix cancer.; Cochrane review abstract and plain language summary. Cochrane Database of Systematic Reviews 2005, Issue 4.; 2005
  13. Elit L, Fyles AW, Devries MC, et al; Follow-up for women after treatment for cervical cancer: a systematic review. Gynecol Oncol. 2009 Sep;114(3):528-35. Epub 2009 Jun 26.
  14. Cervical cancer statistics and outlook, Cancer Research UK

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Sean Kavanagh
Current Version:
Peer Reviewer:
Prof Cathy Jackson
Last Checked:
16/05/2012
Document ID:
1927 (v25)
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