Cervical Cancer

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

Cervical cancer is caused by persistent infection with human papillomavirus (HPV) and accounts for one in ten cancers diagnosed in women worldwide. It is usually a squamous carcinoma.

Epidemiology^[1]

Approximately 570,000 cases of cervical cancer and 311,000 deaths from the disease occurred in 2018. Cervical cancer was the fourth most common cancer in women, ranking after breast cancer (2.1 million cases), colorectal cancer (0.8 million) and lung cancer (0.7 million).

The estimated age-standardised incidence of cervical cancer was 13.1 per 100,000 women globally and varied widely among countries, with rates ranging from less than 2 to 75 per 100,000 women. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa. The global average age at death from cervical cancer was 59 years.

Around 30% of cervical cancers are detected through cervical screening in the UK. Cervical cancer is more common in younger women. More than half of the cervical cancer cases in the UK each year are diagnosed in women under the age of 45^[2].

Risk factors

Persistence of HPV infection is the most important factor in developing cervical cancer; HPV is detected in 99% of cervical tumours. There are around 80 types of HPV that are related to cervical cancer. The high-risk types - HPV 16 and 18 - are highly involved in 70% of cervical cancer^[3].

Other risk factors include^[4]:

• Heterosexual women.
• People with multiple sexual partners.
• Smoking.
• Lower income.
• 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.

Pathogenesis

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 cancer

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. 

Presentation

Many cases are detected by screening. However, any symptoms which could be due to cervical cancer require full pelvic examination including use of a speculum. Abnormal vaginal bleeding is the most common symptom of cervical cancer.

One study showed that about a third of young women with cervical cancer present with symptoms but do not see their doctor promptly. Also, many women who present with symptoms to their GPs do not have their cervix visualised^[5].

The first symptoms of established cervical cancer are^[6]:

• 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 chronic kidney disease 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 pre-cancerous lesions but not cancer. If there is any degree of suspicion of cervical cancer 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.

Differential diagnosis^[6]

• Cervicitis.
• Dysfunctional uterine bleeding.
• Cervical erosion (ectropion).
• Pelvic inflammatory disease.
• Endometrial cancer.
• Side-effects of intrauterine contraceptive device (IUCD) use.
• Endometrial hyperplasia.
• Fibroids.
• Atrophic vaginitis.

Investigations

• Premenopausal women presenting with abnormal vaginal bleeding should be tested for Chlamydia trachomatis.
• 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 may be undertaken.
• FBC, renal function tests, LFTs.
• A CT scan of the chest, abdomen and pelvis with contrast is usually preferred to chest X-ray to assess for metastatic disease.
• Positron emission tomography (PET) is also being used increasingly for staging.
• CT and/or MRI scanning of the pelvis and abdomen are often used to stage disease, along with relevant biopsies.
• Examination under anaesthesia is often undertaken with abdominal, vaginal and rectal examination, with or without colposcopy, hysteroscopy, cystoscopy and sigmoidoscopy. Biopsies are taken as necessary. 

Staging^[3]

The staging system of the International Federation of Gynecology and Obstetrics (FIGO) is most commonly used. This classification is based on tumour size, vaginal or parametrial involvement, bladder/rectum extension and distant metastases.

• 0: no evidence of primary tumour.
• Tisb: carcinoma in situ (pre-invasive).
• I: cervical carcinoma confined to the uterus (disregard extension to corpus):
  • IA: invasive carcinoma diagnosed only by microscopy:
    • 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 non-functioning kidney.
• IV: further spread:
  • IVA: tumour invades the mucosa of the bladder or rectum and/or extends beyond the true pelvis.
  • IVB: distant metastases.

The vast majority of women are diagnosed with early-stage cancers.

Management^[7]

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.

As cervical cancer often affects women of childbearing age, fertility-sparing surgery is an important issue when considering treatment options.

Depending on stage, primary treatment of cervical cancer consists of surgery, radiotherapy or a combination of radiotherapy and chemotherapy.

Surgical

The extent of surgery will be dictated by the tumour stage, the age of the patient and comorbidities. The patient's wishes regarding fertility and management options need to be considered. For example:

• In stage IA1 disease, standard treatment consists of conisation with free margins or simple hysterectomy (according to the patient's age and future fertility choices).
• In stage IA2 disease, local excision can be offered to preserve fertility or extrafascial hysterectomy; however, there is a risk of pelvic lymph node involvement of approximately 5% and bilateral pelvic lymphadenectomy is usually recommended.
• Radical trachelectomy (cervicectomy) is the treatment of choice in women with early-stage cervical cancer wishing to preserve fertility^[8]. Radical trachelectomy can be performed with a vaginal, abdominal or laparoscopic/robotic approach.
• Intraoperative and postoperative complication rates are similar to radical hysterectomy. Approximately 15% of patients develop cervical stenosis and this can lead to dysmenorrhoea or infection.
• Laparoscopic hysterectomy and lymphadenectomy are offered to women not wishing to retain their fertility. The presence of positive lymph nodes indicates the need for adjuvant chemoradiotherapy. The National Institute for Health and Care Excellence (NICE) has issued interventional procedures guidance for minimally invasive radical hysterectomy for early stage cervical cancer^[9]. Compared with open hysterectomy surgery, disease-free and overall survival is lower for tumours 2 cm or larger, so this procedure should not be used in these circumstances. ESMO agrees that radical hysterectomy performed by laparoscopy or robot-assisted surgery cannot be regarded as the preferred treatment in comparison with open surgery in patients with FIGO stage IA2, IB and IIA or tumours smaller than 2 cm^[10]. 
• Stages IB and IIA cervical cancer can be cured by radical surgery including pelvic lymphadenectomy or radiotherapy. The two procedures are equally effective but differ in terms of morbidity and type of complications.
• Radical surgery is associated with significant morbidity and complications. Morbidity may be minimised by using minimally invasive (laparoscopic or robotic) routes.
• Radical (Wertheim's) hysterectomy:
• This aims to provide definitive treatment for invasive, infiltrating and early metastatic cancer.
• 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

• Generally, a combination of external beam therapy and intracavity brachytherapy is used.
• Brachytherapy is an important part of definitive radiotherapy shown to improve overall survival^[11].
• A Cochrane review has recommended the use of high-dose-rate intracavity brachytherapy for all clinical stages of cervical cancer^[12].
• Currently women with stage IB2 to III are given non-surgical treatment (chemoradiation).
• A Cochrane review found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone^[13].

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 settle 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.

Chemotherapy

• Many women with cervical cancer receive chemotherapy, either adjuvant, concurrent with radiation or palliative^[14].
• Cisplatin-based chemotherapy is most commonly given.
• Compared with concurrent chemoradiotherapy, neoadjuvant chemotherapy followed by radical hysterectomy has been shown to achieve comparable survival outcomes for patients with FIGO stage IIB cervical cancer, but with fewer radiotherapy complications^[15].

Follow-up

• There is currently no consensus regarding the length and frequency of follow-up for patients treated for cervical cancer.
• Colposcopy and cervical cytology are not recommended for follow-up.
• It should be noted that in women with cancer-related hysterectomy, the vaginal vault cytology has a low efficacy for the early detection of vaginal recurrence and is not recommended^[16].
• Patients should usually return to annual population-based screening after five years of recurrence-free follow-up.

Prognosis^[4]

The death rate from cervical cancer dropped significantly in the last 40 years. This is believed partly to be a result of improved treatment and early detection through the cervical screening programme. In England and Wales, after diagnosis:

• More than 80% of women survive for one year or more.
• More than 65% of women survive for five years or more.
• Almost 65% of women survive for 10 years or more.

Prognosis correlates with stage, histological diagnosis, socio-economic status and age at presentation. Five-year survival by stage of the tumour:

• Stage IA1: 100%.
• Stage IB2-IIB: 50–70%.
• Stage III: 30-50%.
• Stage IV: 5-15%.

Prevention

• See the separate article Cervical Screening (Cervical Smear Test).
• See the separate article Human Papillomavirus (HPV) Vaccination.

Self-sampling tests have been suggested to improve screening uptake^[17].