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Cervical cancer is a malignancy of the cervix. Worldwide, it is the second most common cancer of women. It may present with vaginal bleeding but symptoms may be absent until the cancer is in advanced stages, which has made cervical cancer the focus of intense screening efforts utilizing the Pap smear.
Signs and symptoms
The early stages of cervical cancer may be completely asymptomatic (Canavan & Doshi, 2000). Vaginal bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of malignancy. In advanced disease, metastasis may be present in the abdomen, lungs or elsewhere.
The possibility to identify premalignant changes on a cervical smear has made screening the major cause for referral of women with possible cervical neoplasia. In many countries, women are advised to have a regular Pap smear to check for premalignant changes. Recommendations for how often a Pap smear should be done vary from once a year to once every five years. If cervical cancer is detected early, it can be treated without impairing fertility. Consistently abnormal smears may be a reason for further diagnosis despite complete absence of symptoms.
Diagnosis is made by doing a biopsy of the cervix, which often involves colposcopy, or a magnified visual inspection of the cervix aided by using an acetic acid solution to produce color changes in precancerous or cancerous areas. A Pap smear is insufficient for the diagnosis. Many researchers recommend that since more than 99% of invasive cervical cancers worldwide contain human papillomavirus, HPV testing should be carried out together with routine cervical screening (Walboomers et al, 1999).
Further diagnostic procedures are loop electrical excision procedure (LEEP) and conisation , in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe dysplasia.
Cervical cancer is staged by the FIGO staging system, which is based on clinical examination, rather than surgical findings. It allows only the following diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.
The TNM staging system for cervical cancer is analagous to the FIGO stage.
- Stage 0 - full-thickness involvement of the epithelium without invasion into the stroma (carcinoma in situ)
- Stage I - limited to the uterus
- IA - diagnosed only by microscopy; no visible lesions
- IA1 - stromal invasion less than 3 mm in depth and 7 mm or less in horizontal spread
- IA2 - stromal invasion between 3 and 5 mm with horizonal spread of 7 mm or less
- IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizonal spread of more than 7 mm
- IB1 - visible lesion 4 cm or less in greatest dimension
- IB2 - visible lesion more than 4 cm
- IA - diagnosed only by microscopy; no visible lesions
- Stage II - invades beyond uterus
- IIA - without parametrial invasion
- IIB - with parametrial invasion
- Stage III - extends to pelvic wall or lower 1/3 of the vagina
- IIIA - involves lower 1/3 of vagina
- IIIB - extends to pelvic wall and/or causes hydronephrosis or non-functioning kidney
- IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis
- IVB - distant metastasis
Note that the FIGO stage does not incorporate lymph node involvement in contrast to the TNM staging for most other cancers.
For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage but is not to replace the original clinical stage.
For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.
The American Cancer Society provides the following list of risk factors for cervical cancer: human papillomavirus infection, smoking, HIV infection, chlamydia infection, dietary factors, oral contraceptives, multiple pregnancies, low socioeconomic status, use of the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.
The presence of strains 16, 18 and 31 of human papillomavirus (HPV) is the prime risk factor for cervical cancer, and Walboomers et al. (1999) reported that the presence of HPV is a necessary condition for the development of cervical cancer. A virus cancer link with HPV has been found to trigger alterations in the cells of the cervix, leading to the development of cancer. The E6 gene introduced by the virus inhibits the p53 gene, the central cellular switch for apoptosis (the process by which damaged cells kill themselves). The mitosis rate accelerates, and the cell accumulates more DNA damage that makes it capable of invading other tissues.
Genital warts are caused by different HPV types, and are not related to cervical cancer.
The medically accepted paradigm is that HPV can be considered a sexually transmitted disease and that use of condoms could prevent transmission. It is thought to grow preferentially in the epithelium of the glans penis, and scrupulous washing and cleaning of this area may be preventative. The position on circumcision is controversial: some researchers argue that routine neonatal circumcision is an acceptable way of preventing various diseases (which include cervical carcinoma); others maintain that the benefits do not outweigh the risks.
Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the lymph nodes are removed as well. An alternative for patients who desire to maintain fertility is a local surgical procedure such as a LEEP or cone biopsy .
Early stages (IB1 and IIA less than 4cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). For patients treated with surgery who have high risk features found on pathologic examination, radiation therapy with or without chemotherapy is given in order to reduce the risk of relapse.
Larger early stage tumors (IB2 and IIA more than 4cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.
Worldwide, cervical cancer is the second most common cancer in women (after breast cancer) and is the third leading killer (behind breast and lung cancer). It affects about 16 per 100,000 women per year and causes death in about 9 per 100,000 per year.
In the United States, however, cervical cancer is only the 8th most common cancer of women. About 12,800 women in the United States are diagnosed with cervical cancer and about 4,800 die each year (Canavan & Doshi, 2000). Among gynecological cancers it ranks behind endometrial cancer and ovarian cancer. The incidence and mortality figure for the U.S. are about half that of the rest of the world, a difference which can be attributed in part to the success of screening with the Pap smear.
In Great Britain the incidence of cervical cancer has reached alarming proportions in that the mortality in England and Wales in women younger than 35 years rose three-fold from 1967 to 1987. In a study published in 2004 (Peto J et al) scientists from the London School of Hygiene and Tropical Medicine found that had it not been for effective cervical screening, one in 65 of all British women born since 1950 would have died from cancer of the cervix.
A study published in 2002 (Castellsagué et al) reports that male circumcision can reduce the risk of penile human papillomavirus (HPV) infection in the man, and as a result that of cervical cancer in his female partner. The authors do state that "it would not make sense to promote circumcision as a way to control cervical cancer in the United States, where Pap smears usually detect it at a treatable stage". In contrast to this claim, Menczer (2004) quotes research that male circumcision probably does not contribute to a lower incidence of cervical cancer in Jewish populations.
Epidemiologists working in the early 20th century noted that:
- Cervical cancer was common in female sex workers.
- It was rare in nuns, except for those who had been sexually active before entering the convent.
- It was more common in the second wives of men whose first wives had died from cervical cancer.
- Its was rare in Jewish women.
This led to the deduction that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1950s and 1960s put the blame on smegma (e.g. Heins et al 1958), but it wasn't until the 1970s that human papillomavirus (HPV) was identified. It has since been demonstrated that HPV is implicated in over 90% of cervical cancers.
A bi-valent vaccine to prevent HPV infection has been developed and tested (Harper et al 2004). It confers immunity against the two (thus, bi-valent) HPV strains 16 & 18. This vaccine, when it is licenced and goes into production, could substantially reduce the incidence of HPV infection, the incidence of cervical cancer, and mortality (Lehtinen & Dillner 2002).
- What are the risk factors for cervical cancer? (American Cancer Society).
- Canavan TP, Doshi NR. Cervical cancer. Am Fam Physician 2000;61:1369-76. Fulltext. PMID 10735343.
- Castellsagué X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith JS, Herrero R, Moreno V, Franceschi S; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Male circumcision, penile human Papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002;346:1105-12. Fulltext. PMID 11948269.
- Heins HC, Dennis EJ, Pratt-Thomas HR. The possible role of smegma in carcinoma of the cervix. Am J Obstet Gynec 1958:76;726-735. PMID 13583012.
- Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G; GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364(9447):1757-65. PMID 15541448.
- Menczer J. The low incidence of cervical cancer in Jewish women: has the puzzle finally been solved? Isr Med Assoc J 2003;5:120-3. PDF. PMID 12674663.
- Lehtinen M, Dillner J. Preventive human papillomavirus vaccination. Sex Transm Infect 2002;78:4-6. Fulltext. PMID 11872848.
- Peto J, Gilham C, Fletcher O, Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004;364:249-56. PMID 15262102.
- Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-9. PMID 10451482.
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