Carcinoma of the cervix is the most common gynaecological malignancy in women worldwide, and the most common cause of cancer death in women. 85% of cases are squamous cell carcinoma. The next major group is adenocarcinoma; the remaining types of carcinoma are all rare.
The incidence of cervical cancer varies considerably over the world. In Australia, there is an incidence of 7.1/100,000 women. This is in contrast to Africa, Central and Southern America and South East Asia, where incidence levels can be as high as 50/100,000. This distribution has a significant relationship between the use of Pap smear screening in these countries.
In the past cervical cancer was the most common cause of cancer death in women in developed countries; this has changed with the introduction of Pap smear tests. Death rates are now 1/3rd of previous levels.
Aetiology and Pathogenesis
Human Papilloma Virus (HPV) has been established as the cause of cervical cancer. The development of cancer is linked to three aspects:
- Contraction of HPV (associated with high number of sexual partners, young age of first intercourse and high parity)
- Immunodeficiency (eg. AIDS or transplanted patients)
- Other carcinogens (eg. smoking)
HPV infects immature (basal) squamous cells. In the female genital tract, these are most easily accessible at the transformation zone of the cervix where the stratified squamous epithelium of the ectocervix changes into the simple columnar epithelium of the endocervix. HPV is unable to infect the mature squamous cell above the basal layer. This reflects the varying incidence of HPV induced carcinoma in the female genital tract.
The most commonly implicated HPV type is 16, followed by 18. Other types can induce carcinoma but with much lower frequency.
Risk factors are divided into:
- Those that increase infection rates with HPV
- Those that inhibit clearance of HPV infection
In the first group are behaviours that increase the risk of contracting HPV, typically multiple sex partners, earlier onset of intercourse, and poor hygiene. The second group includes factors such as smoking and immunodeficiency, which prevent the normal clearance of the virus. Male circumcision has been shown to reduce HPV infectivity and its persistence. High parity and oral contraceptive use may reduce the patient's ability to clear the HPV infection.
Cervical Intraepithelial Neoplasia
Cervical carcinoma is preceded by cervical intraepithelial neoplasia in most cases. There are three grades of CIN; CIN 1 is often referred to as a low grade squamous intraepithelial lesion whereas CIN 2 and CIN 3 are high grade:
- The features of squamous dysplasia include larger nuclei, hyperchromatism, granular appearance of the nucleus, and perinuclear halo - these changes are referred to as koilocytic atypia.
- CIN 1 involves the lower third of the epithelium, nuclei are typically < 1/3rd of the cell size, and koilocytic changes are present in the lower third of the epithelium only. Importantly, CIN 1 does not always progress to cervical cancer and may regress spontaneously (60% of cases). 10% of these lesions progress to CIN 2 or CIN 3.
- CIN 2 occurs when there is involvement of the lower two thirds of the epithelium, with anaplastic features including mitoses occuring in the lower levels. CIN 2 only regresses in 30% of cases and 10% transform into cervical cancer.
- CIN 3 involves the upper third of the epithelium and severe cases could be classified as carcinoma in situ.
Helpful staining for CIN cases are p16 and Ki-67. p16 is overexpressed in cells attempting to control unregulated proliferation by activating RB1; however this protein is deactivated by the viral E7 protein and therefore it is ineffective. Ki-67 is expressed in mitotically active cells and can be helpful for detecting proliferating cells in the upper parts of the epithelium if mitoses are not visible.
Cervical cancers is notable for a low rate of haematogenous metastases, and may remain localised to the pelvis and lymph nodes for a significant period.
Patients typically present with vaginal bleeding or dyspareunia. Most patients with cervical cancer are those who have avoided screening programs. Rarely the disease may be picked up incidentally during pregnancy related assessments.
Examination is critically important, particularly for staging. Examination under anaesthesia is required in all cases. This allows determination of visibility (IA versus IB), size (IB1/IIA1 vs IB2/IIA2), parametrial involvement (IIB), lower vaginal involvement (IIIA), side wall involvement (IIIB), and invasion of adjacent structures (IVA). Sigmoidoscopy and cystoscopy are required in all cases to determine adjacent tissue involvement.
Imaging with MRI is preferred as it gives improved delineation of the tumour mass within the pelvis.
Macroscopically the tumour may appear exophytic and ulcerated. Less commonly, there is deep cervical invasion without an obvious exophytic component, giving rise to a barrel shaped cervix.
Squamous Cell Carcinoma
Microscopically, the tumour infiltrates through the normal cervical stroma in strands or nests of epithelial neoplastic cells. There may be keratin pearls (keratinising type), intercellular bridges and intracellular keratin (non-keratinising type) or basaloid appearance (small cells with minimal keratinisation). Less common variants include verrucous, warty and lymphoepithelial types.
There are several microscopic adenocarcinoma variants. By far the most common is the mucinous adenocarcinoma, where cells contain intracytoplasmic mucin; the most common form of mucinous adenocarcinoma is the endocervical type. Other mucinous carcinomas (intestinal, signet ring etc) can occur but are much rarer. Finally, other adenocarcinomas that may occur in the endometrium may also occur within the cervix, such as endometrioid, serous papillary, and clear cell adenocarcinomas.
Poorly differentiated neuroendocrine carcinoma may arise within the cervix very rarely (1-5% of cases). It appears as sheets, trabeculae or nests of small, malignant cells. Well differentiated neuroendocrine tumours may also occur with an organoid appearance.
TP53 deactivation appears to be an important event in the pathogenesis of cervical cancers, either due to HPV E6 protein deactivation or direct mutation. Loss of heterozygosity is common.