Cervical cancer

Cervix and uterus

The cervix is the lower, narrow end of the uterus (the hollow, pear-shaped organ where a fetus grows). The cervix leads from the uterus to the vagina (birth canal).

Cervical cancer commonly develops slowly over time. Before cancer appears in the cervix, the cells of the cervix go through changes known as dysplasia, in which cells that are not normal begin to appear in the cervical tissue. Later, cancer cells start to grow and spread more deeply into the cervix and to surrounding areas.

Infection of the cervix with human papillomavirus (HPV) is the most common cause of cervical cancer. Not all women with HPV infection, however, will develop cervical cancer. Women who do not regularly have a Pap smear to detect HPV or abnormal cells in the cervix are at increased risk of cervical cancer.

Other possible risk factors include the following:

• Giving birth to a number of children.
• Having a number of sexual partners.
• Having first sexual intercourse at a young age.
• Smoking cigarettes.
• Oral contraceptive use ("the Pill").
• Weakened immune system.

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. Most scientific studies point to human papillomavirus (HPV) infection as a necessary pre-requisite for development of cervical cancer. Treatment is with surgery (including cryosurgery) in early stages and chemotherapy and radiotherapy in advanced stages of the disease. A effective vaccine for the two most common strains of HPV has recently been licenced (see below).

Signs and symptoms

The early stages of cervical cancer may be completely asymptomatic (Canavan andamp; Doshi, 2000). Vaginal bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of malignancy. In advanced disease, metastases may be present in the abdomen, lungs or elsewhere.

The possibility to identify precancerous changes on a cervical smear has made screening the major cause for referral of women with possible cervical neoplasia. In a number of countries, women are advised to have a regular Pap smear to check for precancerous changes.[1] 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

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 premalignant or malignant areas. A Pap smear is insufficient for the diagnosis. A number of scientists 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). However, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers.

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.

Staging

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 analogous 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 horizontal spread of 7 mm or less
  • IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizontal spread of more than 7 mm.
    • IB1 - visible lesion 4 cm or less in greatest dimension
    • IB2 - visible lesion more than 4 cm
• 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 precancerous dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.

Pathophysiology

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 cervical intraepithelial neoplasia and 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, officially endorsed by the American Cancer Society and other organisations, is that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease. Not all women infected with HPV also develop cervical cancer. Use of condoms will not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. HPV 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 scientists 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.

Treatment

Microinvasive cancer (stage IA) is commonly 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 treatment. Radiation treatment 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 treatment 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 treatment and cisplatin-based chemotherapy, hysterectomy (which then commonly requires adjuvant radiation treatment), or cisplatin chemotherapy followed by hysterectomy.

Advanced stage tumors (IIB-IVA) are treated with radiation treatment and cisplatin-based chemotherapy.

Epidemiology

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 andamp; Doshi, 2000). Among gynecological cancers it ranks behind endometrial cancer and ovary 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.[2]

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. As per a research findings published in 2004 (Peto J et al) researchers 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 (Castellsague 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 commonly 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.

History

Epidemiologists working in the early 20th century noted that:

1. Cervical cancer was common in female sex workers.
2. It was rare in nuns, except for those who had been sexually active before entering the convent.
3. It was more common in the second wives of men whose first wives had died from cervical cancer.
4. It was rare in Jewish women.[3]

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 all cervical cancers. Specific viral subtypes implicated are HPV 16, 18 and 33.

Vaccine

A bi-valent vaccine to prevent HPV infection has been developed by Israel and tested (Harper et al 2004). It confers immunity against the two (thus, bi-valent) HPV strains 16 andamp; 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 andamp; Dillner 2002).

References

• Canavan TP, Doshi NR. Cervical cancer Am Fam Clinician 2000;61:1369-76. Fulltext. PMID 10735343.
• Castellsague 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.