Cervical Cancer

Cancer of the cervix – the neck of the womb that opens into the vagina – arises most frequently (~80% of cases) in the layer of epithelial cells that lines the cervix (squamous cell cervical cancer). The other common form (~15%) is in the glandular cells of the cervix (adenocarcinoma).

Cervical cancer is the eighth most common cancer worldwide, with over half a million new cases and more than 250,000 deaths annually. It is the leading cause of cancer deaths in women in the developing world. Cervical cancer only develops as a result of infection of epithelial cells that form the skin or mucous membranes of the cervix by human papilloma virus (HPV), as indicated by the fact that HPV is detectable in over 99% of cervical tumours. HPV infection can also cause cancers of the throat, genitals and anus and it contributes between 3.7 and 5% of the global burden all cancers.

In 1928 George Papanicolaou discovered that vaginal smears can reveal cervical cancer which led to the Pap smear test for carcinomas in the female genital tract. Harald zur Hausen won the Nobel Prize in Physiology or Medicine in 2008 for showing the link between cervical cancer and human papillomavirus (HPV) types 16/18. The first HPV vaccine (Gardasil) entered clinical trials in 2002.

New cases/year

World 2008: 530,000;

USA 2011 (est): 12,710; UK 2008: 2,938

Deaths/year

World 2008: 275,000;

USA 2011 (est): 4,290; UK 2008: 957

Risk factors Infection by human papillomavirus (HPV): typically transmitted by sexual contact, infecting the anogenital region. Transmission is by skin contact – penetration not required). 50-80% of ALL sexually active women have been infected. However, only 10-20% of infected women develop cancer.Available data shows ~60% men infected (though the only data set is for a mixture of Brazilian, Mexican and Hispanic USA males).Smoking doubles the risk.
Symptoms Few in the early stages although vaginal bleeding or discharge may occur. Advanced stages may be associated with loss of appetite/weight, pain, heavy vaginal bleeding and fatigue. The most common sign of genital HPV infection are genital or anal warts (condylomata acuminata or venereal warts), 90% of which are caused by HPV 6 and 11.
Staging TNM system is used (see Tumour staging) or the International Federation of Gynecology and Obstetrics (FIGO) staging system:Stage 0: epithelium with no invasion (carcinoma in situ)Stage I: limited to the cervixStage II: invades beyond cervix

Stage III: extends to pelvic wall or lower third of the vagina

Stage IV: extends outside the vagina

Classification

Smear testing detects abnormal cells (pre-malignant change) that have the potential to progress to cancer. Abnormal smear tests are graded from mild to severe dysplasia depending on the degree that cells have progressed towards a cancerous state. Mild dysplasia often returns to normal within two years. Moderate to severe dysplasia will prompt a colposcopy that can more accurately grade the pre-malignant change using CIN (cervical intraepithelial neoplasia) grading. For pre-malignant changes the CIN (cervical intraepithelial neoplasia) grading defines progression from normal to CIN I (low grade / mild) through CIN II to CIN III (precursor of invasive squamous cell cervical carcinoma).

Major gene mutations

The oncoproteins E6 and E7 of high-risk HPV subtypes inactivate p53 and the retinoblastoma protein, thereby overcoming normal cell cycle control. This leads to high-grade intraepithelial lesions, abnormal growths that are non-invasive and that usually disappear, indicating that HPV infection is not sufficient to cause cervical cancer. Additional factors are therefore required to drive progression to invasive carcinoma. Other than mutations in the STK11 tumour suppressor gene in some cancers, genetic alterations or other agents that cooperate with HPV have not been identified.

Vaccination

Cervarix (v. HPV 16/18) & Gardasil (v. HPV 6/11/16/18). New vaccine being developed that may be effective against more than 90% of HPV types. Prophylactic efficacy approximately 100%.

Treatment

Surgery may be effective for very early stage disease. Radiotherapy is also used. There are few chemotherapy options.

Side effects None serious from either Cervarix or Gardasil.
Prognosis

The duration of immunity is at least six years.

For further information on cervical cancer consult the Royal College of Obstetricians and Gynaecologists.