Contents
Introduction
Cervical carcinoma is a malignant tumour of the epithelium of the cervix. The overall incidence is around 8-9 per 100,000 per year. A wide age range can be affected but the peak incidence is in the fourth decade; a second, smaller peak occurs in women over 70 years. The incidence in the United Kingdom has been falling over the last few decades. The disease is most common in Africa, Central America and South America.
Over 99% of cases of cervical carcinoma are caused by the human papilloma virus (HPV). The human papilloma virus is transmitted by the sexual route and from this perspective cervical carcinoma can be viewed as a sexually transmitted disease. Most of the risk factors for cervical carcinoma all revolve around increased risk of acquisition of HPV and an increased exposure time.
- Early age at first intercourse
- Increased frequency of intercourse
- Multiple partners
- Early first pregnancy
- High number of pregnancies
- Prostitution
- Low socio-economic status
- Impaired immunity
- Smoking
Pathology
Around 85% of carcinomas of the cervix are squamous cell carcinomas. The vast majority of the remainder are adenocarcinomas. Small cell carcinomas, neuroendocrine carcinomas and adenosquamous carcinomas chip in with most of the rest. Non-carcinomatous malignancies are rare but melanoma, lymphoma and sarcomas can all try their hand.
Both squamous cell carcinoma and adenocarcinoma form an infiltrative, nodular mass which may or may not also be exophytic and polypoid. Adenocarcinomas arise in the endocervical canal so can be hidden from view via a speculum or colposcope.
Local invasion is into the isthmus then body of the uterus, the vagina, bladder, rectum and ureters.
Lymph node metastases can occur early; the local lymph nodes are the paracervical, parametrial, internal iliac, obturator, external iliac, common iliac, presacral and lateral sacral. Distant metastases are a feature of late disease. The liver and lungs are first in the firing line.
The human papilloma virus is a risk factor for both squamous cell carcinomas and adenocarcinomas. Numerous different types of HPV exist and are divided into low risk and high risk classes with regard to cervical carcinoma. Around 70% of cases of cervical carcinoma are due to HPV types 16 and 18. Types 31 and 33 fill in most of the gaps after 16 and 18 but types 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are also high risk.
Most infections with HPV resolve within two years. However, up to 10% may persist. Some of these can progress to
cerivcal intraepithelial neoplasia. Some cases of low grade CIN evolve into high grade CIN and some of these cases of high grade CIN progress to carcinoma.
The human papilloma virus acts as a risk factor for carcinoma by interfering with the regulation of the cell cycle and the cell's tumour suppressor mechanisms. HPV produces various proteins and of these, the E6 and E7 proteins are the carcinogenic culprits. The E6 protein promotes the degradation of the tumour suppressor gene p53 and also interferes with the function of p21; p21 is a cyclin dependent kinase inhibitor which inhibits the cyclin-CDK2 and cyclin-CDK4 complexes and thus halts the cell cycle. The E6 protein thus removes one of the regulatory mechanisms for cell growth and also renders the cell more susceptible to sustained DNA damage and to the transmission of those mutations to its daughter cells.
The E7 protein disrupts the function of the retinoblastoma protein by causing it to lose its regulatory grip on the E2F transcription factor. Thus, control over the cell cycle is further compromised.
Clinical Features
The early stages of cervical carcinoma are often asymptomatic and early tumours may only be detected by the cervical screening programme. Nevertheless there may be postcoital bleeding, dyspareunia or lower abdominal pain. Postmenopausal women may have postmenopausual bleeding. More advanced disease can present with haematuria or rectal bleeding. High stage disease can also cause renal failure by obstruction of one or both ureters.
General, non-specific symptoms such as malaise, anorexia and weight loss may be encountered.
On examination the tumour may be visible or palpable. Adenocarcinomas may be hiding in the endocervical canal and may therefore not be visible during a speculum examination or by coloposcopy.
Staging
Cervical carcinoma is staged by the FIGO and TNM systems. The criteria for the stages are the same but where the TNM system would use the format pT followed by an Arabic numeral, with or without a suffix, the FIGO system employs Roman numerals. For example, pT1A1 in the TNM system would be FIGO state IA1 and pT2a becomes stage IIA.
|
T1a1
|
Carcinoma diagnosed only by microscopy
Tumour invasion no greater than 3mm in depth and no greater than 7mm in horizontal extent
|
|
T1a2
|
Tumour diagnosed only by microscopy
Stromal invasion more than 3mm but no more than 5mm and horizontal extent no more than 7mm.
|
|
T1b1
|
Clinically visible lesion that is confined to the cervix or tumour diagnosed by microscopy that exceeds the size limits of stage pT1a2. The tumour is no more than 40mm in size
|
|
T1b2
|
Clinically visible lesion that is confined to the cervix or tumour diagnosed by microscopy that exceeds the size limits of stage pT1a2. The tumour is more than 40mm in size
|
|
T2a
|
Tumour invades beyond the uterus but not to the pelvic wall or lower third of the vagina, without parametrial invasion
|
|
T2b
|
Tumour invades beyond the uterus but not to the pelvic wall or lower third of the vagina, with parametrial invasion
|
|
T3a
|
Tumour involves the lower third of the vagina but not the pelvic wall
|
|
T3b
|
Tumour extends to the pelvic wall or causes hydronephrosis or a non-functioning kidney
|
|
T4
|
Tumour invades the mucosa of the bladder or rectum or extends beyond the true pelvis
|
|
N0
|
No lymph node metastases
|
|
N1
|
Regional lymph node metastasis
|
|
M0
|
No distant metastases
|
|
M1
|
Distant metastases
|
The FIGO system uses stage IVA for pT4 and stage IVB for pM1.
Stromal invasion refers to the depth of invasion of the carcinoma from the base of the epithelium from which the tumour originates and is defined as the distance from the epithelial stromal junction of the adjacent most superficial epithelial papilla to the deepest point of invasion.
Cut Up
The entire cervix should be embedded in a hysterctomy performed for cervical carcinoma. Inking of the circumferential resection / parametrial margin is prudent; four colours can be used for clarity (anterior right, anterior left, posterior right, posterior left).
The cervix can be bread sliced. The first and last slice can then be further divided into cruciate sections.
The parametrium should be embedded in its entirety.
The remainder of the uterus is sampled in the
standard fashion. Extension of the carcinoma into the body of the uterus does not affect the stage.
Investigations
The investigation of cervical carcinoma follows the general pattern of investigation of tumours. The histological diagnosis is usually obtained via a punch biopsy of LLETZ. Some carcinomas are diagnosed on screening smears but would typically proceed to confirmation by a histopathological diagnosis.
Imaging of the tumour and staging is by CT; MRI may be employed as a supplement in some cases.
The possibility of renal impairment due to invasion of the ureters gives an additional justification for checking the urea and electrolytes.
Treatment
The mainstay of treatment is radical hysterectomy, which may be supplemented with removal of the local lymph nodes, although stage three and four disease requires chemoradiotherapy instead. However, hysterectomy renders the patient infertile and a significant number of the patients are premenopausual women who may wish to start or continue their family. In women who wish to preserve their fertility and have low stage tumours (typically no worse than stage IA2 or an early IB1) a trachelectomy can be performed instead. A trachelectomy is removal of the cervix while leaving the body of the uterus behind. Trachelectomy is not necessarily available in all centres.