Cervical Carcinoma

Synonym: Cervical cancer, cancer of the (uterine) cervix, carcinoma of the (uterine) cervix

Worldwide cervical carcinoma is the second commonest female malignancy. In the UK it has been estimated that one in 80 of the 8 million British women born between 1951 and 1970 will be saved from premature death by the cervical screening programme.¹
During 2004 there were 2,221 new cases of invasive cervical cancer diagnosed in England.² It caused 899 deaths in the UK in 2004.

Incidence

UK age-standardised incidence of 8.1/100,000 population in 2002.² Age-standardised mortality rate for UK was 2.8/100,000 in 2004.

Risk factors

• Heterosexual women
• Human papilloma virus (HPV infection), predominantly types 16 and 18 (infection present in around 95% of cases)³
• Women with multiple sexual partners, or partners of promiscuous males
• Smoking
• Lower social class
• Immunosuppression e.g. HIV, post-transplant
• Slight increase in risk with use of combined oral contraceptive
• Non-attendance at cervical screening programme.

Three types of primary tumour are generally seen:

• Bulky, ectocervical tumour fills 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 - disease confined to the epithelium

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

Invasive carcinoma

This breaches the epithelial basement membrane at any point.

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

Many cases are detected by screening. However, symptoms require full pelvic examination including use of speculum.
First symptoms of established cervical carcinoma are:

• Vaginal discharge; varies greatly in amount and can be intermittent or continuous.
• Bleeding; can be spontaneous but may occur after coitus, micturition or defecation in early stages. Patients may ignore this if 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.

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 IUCD use
• Endometrial hyperplasia
• Fibroids
• Atrophic vaginitis

• Pre-menopausal women presenting with abnormal vaginal bleeding should be tested for Chlamydia trachomatis.⁴
• Post-menopausal women should be referred urgently to gynaecology for assessment.
• Colposcopy - allows examination of the visible cervix, usually including the transformation zone
  • Cervix is first cleaned with acetic acid.
  • Cervix can then be inspected, biopsied and treated if necessary.
• Cone biopsy
• FBC (for anaemia) - haemoglobin level should be monitored during chemo-radiotherapy and corrected if it falls below 12 g/dl.
• Renal function tests, LFTs
• Chest X-ray (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 clear picture of primary tumour, local invasion and nodal enlargement

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

• Destruction/excision of abnormal ectocervical epithelium during colposcopy is used for intra-epithelial neoplasia confined to visible ectocervix:
  • Cautery, cryosurgery, laser can be used, but loop diathermy now considered best approach (provides specimen for histology)⁵
  • Patient may experience discomfort, discharge and occasionally bleeding but does not cause cervical incompetence or prevent pregnancy.
  • Healing should be complete in 3 months and visible on repeat colposcopy.
  • Annual follow-up cytology.
• Cone biopsy is needed where cytology suggests CIN with extension above the reach of colposcopy but ectocervical invasive disease is not apparent:
  • 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 then heals quickly with few symptoms apart from light central pelvic discomfort and light vaginal discharge.
  • Providing internal os undamaged pregnancy still possible.
  • This procedure is sufficient if pathology shows that abnormality confined to the epithelium and the margins of both the ectocervix and endocervix are clear of disease.
  • Indefinite annual follow-up cytology.
• 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.⁴
  • This may be performed laparoscopically.
  • Histology may show presence of more extensive disease than expected and patient need post operative radiotherapy. Low risk of postoperative complications.
• Laparoscopic radical hysterectomy is performed for Stage I and IIA cervical cancer.
  • 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.⁶
  • Laparoscopic-vaginal radical hysterectomy should not be offered to patients with tumour diameter greater than 2 cm.⁴
• Radical (Wertheim's) Hysterectomy:
  • Aims to provide definitive treatment for invasive, infiltrating and early metastatic carcinoma.
  • Involves excision of the primary tumour with 1cm margin of healthy tissue and en bloc resection of main pelvic lymph node areas.
  • May involve removal of upper third of 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 bladder and/or rectosigmoid with possible creation of one or two stoma.
  • Patient needs to be relatively fit and able to withstand very destructive surgery.

Radiotherapy

Any patient with cervical cancer considered suitable for radical radiotherapy treatment should have concurrent chemoradiotherapy with a platinum based chemotherapy, if fit enough.⁴

Generally uses combination of external beam therapy and intracavity brachytherapy.

• External beam therapy uses megavoltage with uterus, cervix and primary tumour involved and may extend from true pelvic floor up to upper sacrum and occasionally para-aortic regions. Generally external beam therapy is given at the start of the course of treatment and intra-cavity therapy towards the end. External beam dose is usually 40-60 Gy given in daily doses over 4-6 weeks.
• Intracavity brachytherapy can be given earlier if patient is bleeding heavily and can be used on its own in older patients with stage I or stage IIa, up to 2cm in diameter. Therapy may be low, medium or high dose. The advantage of high dose is that it has a short delivery time (few minutes) compared to 2-3 days for low dose.⁷ This reduces necessary in-patient time and staff exposure to radiation. Intracavity therapy is not suitable for patients with destructive disease or those with a stump carcinoma arising from an earlier hysterectomy.

Complications:

• Most common acute reaction to radiotherapy is 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 sub-acute 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.

Drugs

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 are otherwise suitable for chemotherapy, offer a trial of active chemotherapy.

• If there is an initial symptomatic response e.g. relief of pain and leg oedema together with objective response, then offer full 6-8 month course.
• Only good partial or complete remission in 20-25% patients, and unlikely to last more than 3 years.

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.⁸
• 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.⁹

Approximate 5 year survival depends upon stage.

Patients should be followed up every four months for at least two years.⁴

• Cervical smear, see Cervical Screening.
• A quadrivalent human papillomavirus vaccine against the viral types most likely to cause cervical cancer (types 16 and 18) and genital warts (types 6 and 11) has been developed.
  • It is 95% to 100% efficacious against cervical intraepithelial neoplasia and adenocarcinoma in situ and 99% efficacious against genital warts caused by serotypes in the vaccine.^10,11
  • This accounts for 70% of cervical carcinomas, therefore cervical screening will still be necessary
  • The DOH has recently announced that all girls aged 12-13 years in the UK will receive the vaccine from September 2008.¹²